Androgen receptor antagonists

ABSTRACT

The present invention provides an androgen receptor antagonistic agent and a superior prophylactic or therapeutic agent for hormone-sensitive cancer, which contain a compound of the formula:  
                 
 
wherein, R 1  is a hydrogen atom, a group binding through a carbon atom, a group binding through a nitrogen atom, a group binding through an oxygen atom or a group binding through a sulfur atom, R 2  is a hydrogen atom, a group binding through a carbon atom, a group binding through a nitrogen atom, a group binding through an oxygen atom or a group binding through a sulfur atom, R 3  is a hydrogen atom, a hydrocarbon group which may have substituent(s), an acyl group or a heterocyclic group which may have substituent(s), R 4  is a hydrogen atom, a group binding through a carbon atom, a group binding through a nitrogen atom, a group binding through an oxygen atom or a group binding through a sulfur atom, and R 5  is a cyclic group which may have substituent(s); or a salt thereof, or its prodrug.

TECHNICAL FIELD

The present invention relates to an androgen receptor antagonistic drugwhich has prophylactic and therapeutic effects againstandrogen-dependent diseases by inhibiting male sex hormone androgenreceptor (AR), and whose effects are not influenced by the mutation ofAR.

BACKGROUND

For the therapy of prostate cancer (its proliferation at the early stageis controlled by androgen which is a type of steroid hormone, andtherefore, such kinds of prostate cancer are said to be “an androgen(hormone)-dependent”) which is one of the most serious diseases amongthe male sex hormone-dependent diseases, the first choice aiming at theradical cure is the treatment by means of surgical operation. and/orradiotherapy. However, the endocrine therapy with an LH-RH agonist ismainly selected when surgical operation and radiotherapy cannot beadopted or when a recurrence has occurred after the operation. Further,the adjuvant therapy by using an androgen receptor (AR) antagonistsolely and the MAB (Maximum Androgen Block) therapy, in which an LHRHagonist and an. androgen receptor (AR) antagonist are used incombination, are carried out, and the efficacy of these treatments aresurprisingly remarkable. However, endocrine therapy is not a radicalcure therapy, and there is a possibility that a hormone-independentrecurrent carcinoma is caused as a result of the generation of endocrinetherapy-resistance. (As the mechanism of this resistance generation, itis thought that cancer cells change to have the ability to use othersteroid hormones or the androgen receptor antagonists which are used inthe therapy as an agonist-like ligand. It can be said that such kinds ofprostate cancer are not androgen (hormone)-dependent but androgen(hormone)-independent. Further, in the sense that the cancer cells reactto other steroid hormones or androgen receptor antagonists used for thetherapy and proliferate, it can be said that they are“hormone-sensitive”. If the cancer cells change further, they will nolonger react to the hormones at all, and in this case it can be saidthat they have become hormone-insensitive.

Flutamide and bicalutamide, which are both androgen receptor (AR)antagonists available in the market, are said to become considerablyless effective against a hormone-independent recurrent cancer which hasacquired a system adapted to a mutant AR or a low concentration ofandrogen, and even to change to an agonist. Further, chemotherapeuticagents are not expected to be effective against such type ofhormone-independent cancers, and this is a major problem in thetreatment of the prostate cancer.

In recent years, based on the research progress on hormone-independentdiseases, it has come to be known that, in the disease calledhormone-independent disease, proliferation proceeds by using the signaltransduction system via AR in the same manner as that in thehormone-dependent diseases. It came to be known that change in thesignal transduction system causes an apparent hormone-independentphenomenon. Concretely speaking, when AR mutates, for example, otherthan androgen, glucocorticoid and currently used AR antagonistthemselves come to act as agonists. As a result of some change includingthe change of expression level and/or mutation of AR, the sensitivity ofAR increases, whereby a strong proliferation signal comes to betransmitted by a small amount of androgen. By these changes, presentlyused AR antagonists are being found to be considerably less effective.

If a compound having a strong antagonistic effect against an mutated ARand an AR having increased sensitivity can be found, the compound isexpected to become a drug effective with prostate cancer in thehormone-independent stage.

DISCLOSURE OF INVENTION

The present inventors conducted intensive investigations and found acompound having an excellent antagonistic activity against anatural-type AR as well as a strong inhibitory activity against a mutantAR. In addition, the inventors found that these compounds can beadministered orally, show extremely low toxicity, and therefore aresufficiently satisfactory as pharmaceuticals with AR antagonisticeffects. This invention was completed on the basis of these findings.

The present invention relates to:

-   (1) An androgen receptor antagonistic agent containing a compound of    the formula:    wherein, R¹ is a hydrogen atom, a group binding through a carbon    atom, a group binding through a nitrogen atom, a group binding    through an oxygen atom or a group binding through a sulfur atom, R²    is a hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R³ is a hydrogen    atom, a hydrocarbon group which may have substituent(s), an acyl    group or a heterocyclic group which may have substituent(s), R⁴ is a    hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R⁵is a cyclic group    which may have substituent(s), or a salt thereof, or its prodrug,-   (2) An agent as defined in (1) above, wherein R¹ is a hydrogen atom,    a cyano group, a hydrocarbon group which may have substituent(s), a    group represented by the formula: —COOR⁶¹ (wherein R⁶¹ is a hydrogen    atom or a hydrocarbon group which may have substituent(s)), a group    represented by the formula: —CONR⁷¹R⁸¹ (wherein R⁷¹ and R⁸¹ are the    same or different, each of them is a hydrogen atom or a hydrocarbon    group which may have substituent(s), and R⁷¹ and R⁸¹ are combined    with each other together with the adjacent nitrogen atom to form a    cyclic group which may have substituent(s)), a group represented by    the formula: —COR⁹¹ (wherein R⁹¹ is a hydrogen atom or a hydrocarbon    group which may have substituent(s)) or a group represented by the    formula: —OR¹³¹ (wherein R¹³¹ is a hydrogen atom or a hydrocarbon    group which may have substituent(s));-   (3) An agent as defined in (1) above, wherein R¹ is a cyano group or    a group represented by the formula: —COOR⁶¹ (wherein R⁶¹ is a    hydrocarbon group which may have substituent(s));-   (4) An agent as defined in (1) above, wherein R² is a hydrogen atom,    a cyano group, a hydrocarbon group which may have substituent(s), a    group represented by the formula: —COOR⁶²: (wherein R⁶² is a    hydrocarbon group which may have substituent(s)), a group    represented by the formula: —CONR⁷²R⁸² (wherein R⁷² and R⁸² are the    same or different, each of them is a hydrogen atom or a hydrocarbon    group which may have substituent(s), R⁷² and R⁸² are combined with    each other together with the adjacent nitrogen atom to form a cyclic    group which may have substituent(s)), a group represented by the    formula: —COR⁹² (wherein R⁹² is a hydrogen atom or a hydrocarbon    group which may have substituent(s)), or a group represented by the    formula: —OR¹³² (wherein R¹³² is a hydrogen atom or a hydrocarbon    group which may have substituent(s));-   (5) An agent as defined in (1) above, wherein R² is a C₁₋₆ alkyl    group which may have substituent(s);-   (6) An agent as defined in (1) above, wherein R³ is a C₁₋₆ alkyl    group which may have substituent (s), a C₇₋₁₅ aralkyl group which    may have substituent(s), a heterocyclic group-C₁₋₆ alkyl group which    may have substituent(s), a C₁₋₆ alkyl group-sulfonyl group which may    have substituent(s), a C₆₋₁₄ aryl group-sulfonyl group which may    have substituent(s), a heterocyclic group-sulfonyl group which may    have substituent(s), a C₁₋₆ alkyl group-carbonyl group which may    have substituent(s), a C₆₋₁₄ aryl group-carbonyl group which may    have substituent(s) or a heterocyclic group-carbonyl group which may    have substituent(s);-   (7) An agent as defined in (1) above, wherein R³ is a benzyl group    which may have substituent(s) or a pyridylmethyl group which may    have substituent(s);-   (8) An agent as defined in (1) above, wherein R³ is a heterocyclic    group-methyl group which may have substituent(s));-   (9) An agent as defined in (1) above, wherein R⁴ is a hydrogen atom,    a cyano group, a hydrocarbon group which may have substituent(s), a    group represented by the formula: —COOR⁶⁴ (wherein R⁶⁴ is a hydrogen    atom or a hydrocarbon group which may have substituent(s)), a group    represented by the formula: —CONR⁷⁴R⁸⁴ (wherein R⁷⁴ and R⁸⁴ are the    same or different, each of them is a hydrogen atom or a hydrocarbon    group which may have substituent(s), R⁷⁴ and R⁸⁴ are combined to    each other together with the adjacent nitrogen atom to form a cyclic    group which may have substituent(s)), a group represented by the    formula: —COR⁹⁴ (wherein R⁹⁴ is a hydrogen atom or a hydrocarbon    group which may have substituent(s)) or a group represented by the    formula: —OR¹³⁴ (wherein R¹³⁴ is a hydrogen atom or a hydrocarbon    group which may have substituent(s));-   (10) An agent as defined in (1) above, wherein R⁴ is a C₁₋₆ alkyl    group which may have substituent(s);-   (11) An agent as defined in (1) above, wherein R⁵ is a cyclic    hydrocarbon group which may have substituent(s);-   (12) An agent as defined in (1) above, wherein R⁵ is a C₆₋₁₄ aryl    group which may have substituent(s) or a heterocyclic group which    may have substituent(s);-   (13) An agent as defined in (1) above, wherein R⁵is a C₆₋₁₄ aryl    group which has at least one substituent selected from a group    consisting of a cyano group and a nitro group;-   (14) An agent as defined in (1) above, wherein R¹ is a cyano group,    a C₁₋₆ alkyl group which may have hydroxy, a group represented by    the formula: —COOR^(6′1) (wherein R^(6′1) is a C₁₋₆ alkyl group), a    group represented by the formula: —CONR^(7′1)R^(8′1) “(wherein    R^(7′1) and R^(8′1) are the same or different, each of them is a    hydrogen atom, a C₁₋₆ alkyl group or a C₆₋₁₀ aryl group, R^(7′1) and    R^(8′1) are taken together to form a cyclic group which may have    substituent(s)), a group represented by the formula: —COR^(9″1)    (wherein R^(9″1) is a C₁₋₆ alkyl group, a C₃₋₈ cyclo alkyl group or    a heterocyclic group which may have substituent(s)), R² and R⁴ are    the same or different, and each of them is a hydrogen atom, a cyano    group or a C₁₋₆ alkyl group, R³ is a hydrogen atom or a hydrocarbon    group which may have substituent(s) or a heterocyclic group which    may have substituent(s), R⁵ is an aryl group which may have    substituent(s), a C₃₋₈ cyclo alkyl group which may have    substituent(s) or a heterocyclic group which may have    substituent(s);-   (15) An agent as defined in (1) above, wherein R¹ is a cyano group    or a group represented by the formula: —COOR^(6′1) (wherein R^(6′1)    is a C₁₋₆ alkyl group), R² is a C₁₋₆ alkyl group which may have    substituent(s), R³ is a C₁₋₆ alkyl group which may have    substituent(s), a C₇₋₁₅ aralkyl group which may have substituent(s),    a C₁₋₆ alkyl group-sulfonyl group which may have substituent(s) or a    C₆₋₁₄ aryl group-carbonyl group which may have substituent(s), a R⁴    is a C₁₋₆ alkyl group which may have substituent(s), R⁵ is a C₆₋₁₄    aryl group which may have substituent(s);-   (16) An agent as defined in (1) above, wherein R¹ is a cyano group    or a group represented by the formula: —COOR^(6′1) (wherein R^(6′1)    is a C₁₋₆ alkyl group), R² is a C₁₋₆ alkyl group, R³ is a C₁₋₆ alkyl    group which may have hydroxy, a C₇₋₁₅ aralkyl group, a C₁₋₆ alkyl    group-sulfonyl group or a C₆₋₁₄ aryl group-carbonyl group, R⁴ is a    C₁₋₆ alkyl group, and R⁵ is a C₆₋₁₄ aryl group which may have a    nitro group, a cyano group or a C₁₋₃ acyl group;-   (17) An agent as defined in (1) above, wherein the compound is a    group represented by the formula:    wherein R^(1′) is a cyano group, a C₁₋₆ alkyl group, a group    represented by the formula: —COOR^(6′1′) (wherein R^(6′1′) is a C₁₋₆    alkyl group), a group represented by the formula:    —CONR^(7′1′)R^(8′1′) (wherein R^(7′1′) and R^(8′1′) are the same or    different, and each of them is a hydrogen atom, a C₁₋₆ alkyl group    or a C₆₋₁₀ aryl group), a group represented by the formula:    —C(OH)R^(161′)R^(16′1′) (R^(161′) and R^(16′1′) are the same or    different, and each of them is a hydrogen atom or a C₁₋₆ alkyl) or a    group represented by the formula: —COR^(9″1′) (wherein R^(9″1′) is a    C₁₋₆ alkyl group, a C₃₋₈ cyclo alkyl group or a heterocyclic group    which may have substituent(s)), R¹⁷ is a C₆₋₁₄ aryl group which may    have substituent(s) or a heterocyclic group which may have    substituent(s), R¹⁸ is a nitro group, a C₁₋₆ alkyl group which may    have substituent(s), a halogen atom, a C₁₋₆ alkoxy group, a cyano    group, a carboxyl group, a carboxylic acid ester group, a hydroxy    group or an amide group, X¹ is a bivalent group in which the number    of straight-chained carbon atom(s) is 1 to 5 which may have    substituent(s); or a salt thereof, or its prodrug;-   (18) An agent as defined in (1) above, wherein the compound is    represented by the formula:    wherein R^(1″) is a cyano group or a group represented by the    formula: —COOR^(6″1″) (wherein R^(6″1″) is a methyl group or a ethyl    group), R¹⁹ is a C₆₋₁₄ aryl group which may have substituent(s) or a    heterocyclic group which may have substituent(s), at least one of    R²⁰ and R²¹ is a nitro group or a cyano group, the ring A may    further have substituent(s), and X² is a bivalent group in which the    number of straight-chained carbon atom(s) is 1 to 5 which may have    substituent(s); or a salt thereof, or its prodrug;-   (19) An agent as defined in (1) above, wherein the compound is one    selected from the group consisting of (1) ethyl    1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate or    a salt thereof, (2) methyl    1-benzyl-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate or    a salt thereof, (3) methyl    1-benzyl-4-(4-formylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate or    a salt thereof, (4) methyl    4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole    -3-carboxylate or a salt thereof, (5)    4-(4-cyanophenyl)-2,5-dimethyl-l-(3-pyridylmethyl)-1H-pyrrole    -3-carbonitrile or a salt thereof, (6)    4-(4-cyanophenyl)-2,5-dimethyl-1-((6-methyl-3-pyridyl)methyl)    -1H-pyrrole-3-carbonitrile or a salt thereof and (7)    4-(4-cyanophenyl)-2,5-dimethyl-1-((6-chloro-3-pyridyl)methyl)    -1H-pyrrole-3-carbonitrile or a salt thereof;-   (20) An agent as defined in (1) above, wherein the androgen receptor    is a normal androgen receptor and/or a mutant androgen receptor;-   (21) An agent as defined in (1) above, which is a prophylactic or    therapeutic agent for hormone-sensitive cancer in androgen-dependent    stage and/or androgen-independent stage;-   (22) An agent as defined in (1) above, which is a prophylactic or    therapeutic agent for prostate cancer;-   (23) A compound represented by the formula:    wherein R^(1a) is a hydrogen atom, a group binding through a carbon    atom, a group binding through a nitrogen atom, a group binding    through an oxygen atom or a group binding through a sulfur atom,    R^(2a) is a hydrogen atom, a group binding through a carbon atom, a    group binding through a nitrogen atom, a group binding through an    oxygen atom or a group binding through a sulfur atom, R^(3a) is an    aromatic ring group which may have substituent(s), R^(4a) is a    hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, at least one of    R^(5a) and R^(5aa) is a nitro group, a cyano group or a formyl    group, the ring B may further have substituent(s), and X³ is a    bivalent group in which the number of straight-chained carbon,    atom(s) is 1 to 5, which may have substituent(s); (provided that (1)    ethyl    4-(3-cyanophenyl)-1-(2-naphthylmethyl)-1H-pyrrole-3-carboxylate, (2)    ethyl    4-(3-cyanophenyl)-1-(1-naphthylmethyl)-1H-pyrrole-3-carboxylate, (3)    1-benzyl-3-(3-nitrophenyl)-1H-pyrrole, (4)    1-benzyl-3-methyl-4-(4-nitrophenyl)-1H-pyrrole, (5) tert-butyl    4-ethyl-1-(4-nitrobenzyl)-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate, (6)    tert-butyl    4-ethyl-1-(4-methoxybenzyl)-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate, (7)    tert-butyl    1-benzyl-4-ethyl-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate, (8)    tert-butyl    1-benzyl-4-methyl-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate, (9)    methyl [4-(aminocarbonyl)-5-methyl-3-(4-nitrophenyl)-1-(2-pyridine    -2-ylethyl)-1H-pyrrole-2-yl]acetate, (10)    1-benzyl-N-{2′-[(tert-butylamino)sulfonyl]-1,1′-biphenyl-4-yl}-4-(3-cyanophenyl)-1H-pyrrole-3-carboxamide, (11)    3-{1-[(E)-1-cyano-2-(3,5-dichloro-1-methyl-1H-pyrazole-4-yl)    -2-hydroxyethenyl]-1H-pyrrole-3-yl}benzonitrile, (12) methyl    4-(4-amino-3-nitrophenyl)-1-benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylate, (13)    methyl 1-benzoyl-4-(3-nitrophenyl)-1H-pyrrole-3-carboxylate, (14)    4-[1-benzyl-2-(2-furanyl)-5-phenyl-1H-pyrrole-3-yl]-benzonitrile    and (15) 4-[1-benzyl-2,5-diphenyl-1H-pyrrole-3-yl]-benzonitrile are    excluded) a salt thereof, or its prodrug;-   (24) A compound as defined in (23) above, wherein X³ is a methylene    group which may have substituent(s), R^(3a) is a C₆₋₁₄ aryl group    which may have substituent(s), or a 5- to 14-membered aromatic    heterocyclic group which may have substituent(s) or a salt thereof,    or its prodrug;-   (25) A compound as defined in (23) above, wherein X³ is a methylene    group which may have substituent(s), and R^(3a) is a 5- to    14-membered aromatic heterocyclic group which may have    substituent(s) or a salt thereof, or its prodrug;-   (26) A compound represented by the formula:    wherein R^(1b) is a cyano group or a group represented by the    formula: —COOR^(6′1b) (wherein R^(6′1b) is a C₁₋₆ alkyl group),    R^(2b) is a hydrogen atom or a C₁₋₆ alkyl group, R^(3b) is a C₁₋₆    alkyl group which may have substituent(s), a C₇₋₁₅ aralkyl group    which may have substituent(s), a 5- to 14-membered aromatic    heterocyclic group-C₁₋₆ alkyl group, a group represented by the    formula: —CO—R^(9′3b) (wherein R^(9′3b) is a C₁₋₆ alkyl group which    may have substituent(s), a C₆₋₁₄ aryl group which may have    substituent(s) or a 5- to 14-membered aromatic heterocyclic group    which may have substituent(s)) or a group represented by the    formula: —SO₂—R^(12′3b) (wherein R^(12′3b) is a C₁₋₆ alkyl group    which may have substituent(s), a C₆₋₁₄ aryl group which may have    substituent(s) or a 5- to 14-membered aromatic heterocyclic group    which may have substituent(s)), R^(4b) is a hydrogen atom or a    C₁₋₆alkyl group, at least one of R^(5b) and R^(5bb) is a nitro    group, a cyano group or a formyl group; (provided (1) ethyl    4-(3-cyanophenyl)-1-(2-naphthylmethyl)-1H-pyrrole-3-carboxylate, (2)    ethyl    4-(3-cyanophenyl)-1-(1-naphthylmethyl)-1H-pyrrole-3-carboxylate, (3)    methyl    4-(4-amino-3-nitrophenyl)-1-benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylate, (4)    methyl    4-(4-amino-3-nitrophenyl)-1-butyl-2,5-dimethyl-1H-pyrrole-3-carboxylate, (5)    methyl    4-(4-amino-3-nitrophenyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate, (6)    methyl 1-benzoyl-4-(3-nitrophenyl)-1H-pyrrole-3-carboxylate, (7)    dimethyl 4-(3-nitrophenyl)-1H-pyrrole-1,3-dicarboxylate are    excluded), its salt, or its prodrug;-   (27) A compound as defined in (26) above, wherein R^(1b) is a cyano    group or a group represented by the formula: —COOR^(6′1b) (wherein    R^(6′1b) is a C₁₋₆ alkyl group), R^(2b) is a C₁₋₆ alkyl group,    R^(3b) is a C₁₋₆ alkyl group which may have substituent(s), a C₇₋₁₅    aralkyl group which may have substituent(s), a 5- to 14-membered    aromatic heterocyclic group-C₁₋₆ alkyl group which may have    substituent(s), a group represented by the formula: —CO—R^(9′3b)    (wherein R^(9′3b) is a C₁₋₆ alkyl group which may have    substituent(s), a C₆₋₁₄ aryl group which may have substituent(s) or    a 5- to 14-membered aromatic heterocyclic group which may have    substituent(s)) or a group represented by the formula: —S₂—R^(12′3b)    (wherein R^(12′3b) is a C₁₋₆ alkyl group which may have    substituent(s), a C₆₋₁₄ aryl group which may have substituent(s) or    a 5- to 14-membered aromatic heterocyclic group which may have    substituent(s)), R^(4b) is a C₁₋₆ alkyl group, R^(5b) is a nitro    group, a cyano group or a formyl group or a salt thereof, or its    prodrug;-   (28) A compound as defined in (26) above, wherein R^(3b) is a C₆₋₁₄    aryl-methyl group which may have substituent(s), or a 5- to    14-membered aromatic heterocyclic group-methyl group which may have    substituent(s) or a salt thereof, or its prodrug;-   (29) A compound as defined in (26) above, wherein R^(3b) is a 5- to    14-membered aromatic heterocyclic group-methyl group which may have    substituent(s) a salt thereof, or its prodrug;-   (30) A compound as defined in (26) above, wherein R^(1b) is a cyano    group or a salt thereof, or its prodrug;-   (31) A compound as defined in (26) above, wherein R^(3b) is a benzyl    group which may have substituent(s) or a pyridylmethyl group which    may have substituent(s) or a salt thereof, or its prodrug;-   (32) A compound selected from the group consisting of (1) ethyl    1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate or    its salt, (2) methyl    1-benzyl-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate or    its salt, (3) methyl    1-benzyl-4-(4-formylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate or    its salt, (4) methyl    4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole    -3-carboxylate or its salt, (5)    4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole    -3-carbonitrile or its salt, (6)    4-(4-cyanophenyl)-2,5-dimethyl-1-((6-methyl-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrile    or its salt, and (7)    4-(4-cyanophenyl)-2,5-dimethyl-1-((6-chloro-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrile    or its salt;-   (33) A medicament containing a compound defined in (23) above    or (26) above or a salt thereof, or its prodrug;-   (34) A medicament which comprises a compound represented by the    formula:    wherein R¹ is a hydrogen atom, a group binding through a carbon    atom, a group binding through a nitrogen atom, a group binding    through an oxygen atom or a group binding through a sulfur atom, R²    is a hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R³ is a hydrogen    atom, a hydrocarbon group which may have substituent(s), an acyl    group or a heterocyclic group which may have substituent(s), R⁴ is a    hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through a oxygen    atom or a group binding through a sulfur atom, R⁵ is a cyclic group    which may have substituent(s); or a salt thereof, or its prodrug and    an anticancer drug in combination;-   (35) A medicament as defined in (34) above, wherein the anticancer    agent is an LH—RH derivative;-   (36) A prophylactic or therapeutic agent for a cancer sensitive to a    hormone in androgen-dependent stage and/or androgen-independent    stage comprising a mutant androgen receptor antagonistic drug;-   (37) A prophylactic or therapeutic agent for a cancer sensitive to a    hormone in androgen-dependent stage and/or androgen-independent    stage which comprises mutant androgen receptor antagonistic drug and    an anticancer agent;-   (38) An agent as defined in (37) above, wherein the anticancer agent    is an LH—RH derivative;-   (39) A prophylactic or therapeutic agent for a cancer sensitive to a    hormone in androgen-dependent stage and/or androgen-independent    stage containing a sensitivity-increased androgen receptor    antagonistic drug;-   (40) A prophylactic or therapeutic agent for a cancer sensitive to a    hormone in androgen-dependent stage and/or androgen-independent    stage which comprises a sensitivity-increased androgen receptor    antagonistic drug and an anticancer agent;-   (41) A prophylactic or therapeutic agent as defined in (40) above,    wherein the anticancer agent is an LH—RH derivative;-   (42) A method for antagonizing androgen receptor, which comprises    administering an effective amount of a compound of the formula:    wherein R¹ is a hydrogen atom, a group binding through a carbon    atom, a group binding through a nitrogen atom, a group binding    through an oxygen atom or a group binding through a sulfur atom, R²    is a hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R³ is a hydrogen    atom, a hydrocarbon group which may have substituent(s), an acyl    group or a heterocyclic group which may have substituent(s), R⁴ is a    hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R⁵ is a cyclic group    which may have substituent(s); or a salt thereof, or its prodrug, to    a mammal;-   (43) A method for preventing or treating a cancer sensitive to a    hormone in androgen-dependent stage and/or androgen-independent    stage, which comprises administering an effective amount of a    compound represented by the formula:    wherein R¹ is a hydrogen atom, a group binding through a carbon    atom, a group binding through a nitrogen atom, a group binding    through an oxygen atom or a group binding through a sulfur atom, R²    is a hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R³ is a hydrogen    atom, a hydrocarbon group which may have substituent(s), an acyl    group or a heterocyclic group which may have substituent(s), R⁴ is a    hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R⁵ is a cyclic group    which may have substituent(s); or a salt thereof, or its prodrug, to    a mammal;-   (44) A method for preventing or treating prostate cancer, which    comprises administering an effective amount of a compound    represented by the formula:    wherein R¹ is a hydrogen atom, a group binding through a carbon    atom, a group binding through a nitrogen atom, a group binding    through an oxygen atom or a group binding through a sulfur atom, R²    is a hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R³ is a hydrogen    atom, a hydrocarbon group which may have substituent(s), an acyl    group or a heterocyclic group which may have substituent(s), R⁴ is a    hydrogen atom, a group binding through a carbon atom, a group    binding through a nitrogen atom, a group binding through an oxygen    atom or a group binding through a sulfur atom, R⁵ is a cyclic group    which may have substituent(s); or a salt thereof, or its prodrug, to    a mammal;-   (45) A method as defined in (43) and (44) above in which an    effective amount of an anticancer agent is further administered;-   (46) A method as defined in (45) above, wherein the anticancer agent    is an LH—RH derivative;-   (47) A method for preventing or treating a cancer sensitive to a    hormone in androgen-dependent stage and/or androgen-independent    stage, which comprises administering an effective amount of mutant    androgen receptor antagonistic drug to a mammal;-   (48) A method as defined in (47) above, in which an effective amount    of an anticancer agent is further administered;-   (49) A method as defined in (48) above, wherein the anticancer agent    is an LH—RH derivative;-   (50) A method for preventing or treating a cancer sensitive to a    hormone in androgen-dependent stage and/or androgen-independent    stage, which comprises administering an effective amount of a    sensitivity-increased androgen receptor antagonistic drug to a    mammal;-   (51) A method as defined in (50) above, in which an effective amount    of an anticancer agent is further administered; and-   (52) A method as defined in (51) above, wherein the anticancer agent    is an LH—RH derivative.

BEST MODE FOR CARRYING OUT THE INVENTION

When the compound (I), (I′) or (I″) or a salt thereof has asymmetriccarbon(s), both of optical isomers and racemate are included in thescope of the present invention, and the compound or its salt may beeither a hydrate or an anhydrate.

In the present specification, as the “hydrocarbon group” in the“hydrocarbon group which may have substituent(s)”, there may bementioned, for example, a chain- or a cyclic hydrocarbon group (e.g., analkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, anaryl group, an aralkyl group, etc.). Among these, a chain- or a cyclichydrocarbon group having 1 to 16 carbon atom(s), etc., are preferable.

As the “alkyl group”, for example, a C₁₋₆ alkyl group (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl, etc.), etc., are preferable.

As the “alkenyl group”, for example, a C₂₋₆ alkenyl group (e.g., vinyl,allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, etc.),etc., are preferable.

As the “alkynyl group”, for example, a C₂₋₆ alkynyl group (e.g.,ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.),etc., are preferable.

As the “cycloalkyl group”, for example, a C₃₋₆ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), etc., arepreferable.

As the “aryl group”, for example, a C₆₋₁₄ aryl group (e.g., phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl, etc.), etc., are preferable, and a C₆₋₁₀ aryl group such asphenyl, etc., are more preferable.

As the “aralkyl group”, for example, a C₇₋₁₆ aralkyl group (e.g.,benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.),etc., are preferable, and a C₆₋₁₀-aryl-C₁₋₅ alkyl group such as benzyl,etc., are more preferable.

As the “substituent(s)” in the “hydrocarbon group which may havesubstituent(s)”, there may be mentioned, for example, oxo, a halogenatom (e.g., fluorine, chlorine, bromine, iodine, etc.), a C₁₋₃alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano,a C₁₋₆ alkyl which may be halogenated, a C₂₋₆ alkenyl which may behalogenated, a carboxy-C₂₋₆ alkenyl (e.g., 2-carboxyethenyl,2-carboxy-2-methyl ethenyl, etc.), a C₂₋₆ alkynyl which may behalogenated, a C₃₋₆ cycloalkyl which may be halogenated, a C₆₋₁₄ aryl(e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl, etc.), a C₁₋₈ alkoxy which may be halogenated,a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (e.g., ethoxycarbonylmethyloxy,etc.), hydroxy, a C₆₋₁₄ aryloxy (e.g., phenyloxy, 1-naphthyloxy,2-naphthyloxy, etc.), a C₇₋₁₆ aralkyloxy (e.g., benzyloxy, phenethyloxy,etc.), mercapto, a C₁₋₆ alkylthio which may be halogenated, a C₆₋₁₄arylthio, (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio, etc.), aC₇₋₁₆ aralkylthio (for example, benzylthio, phenethylthio, etc.), amino,a mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino, etc.), amono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino, etc.), a di-C₁₋₆ alkylamino (e.g., dimethylamino,diethylamino, ethylmethylamino, etc.), a di-C₆₋₁₄ arylamino (e.g.,diphenylamino, etc.), formyl, carboxy, carboxy-C₂₋₆ alkenyl,carboxy-C₁₋₆ alkyl, a C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl,etc.), a C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), a C₁₋₆ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl, etc.)., a C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl, etc.), a C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, 3-phenylpropionyl, etc.), a C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl, etc.), a C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl, etc.), a 5- or 6-memberedheterocyclic ring-carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl,furoyl, morpholinocarbonyl, thiomorpholinocarbonyl,piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), carbamoyl,thiocarbamoyl, a mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl, etc.), di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl, etc.), a mono- or a di-C₆₋₁₄aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl, etc.), a mono- or a di- 5- or 6-memberedheterocyclic group-carbamoyl (e.g., 2-pyridylcarbamoyl,3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl,3-thienylcarbamoyl, etc.), a C₁₋₆ alkyl-sulfonyl (e.g., methylsulfonyl,ethylsulfonyl, etc.), a C₁₋₆ alkyl-sulfinyl (e.g., methylsulfinyl,ethylsulfinyl, etc.), a C₆₋₁₄ aryl-sulfonyl (e.g., phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), a C₆₋₁₄ aryl-sulfinyl(e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.),formylamino, a C₁₋₆ alkyl-carbonylamino (e.g., acetylamino, etc.), aC₆₋₁₄ aryl-carbonylamino (e.g., benzoylamino, naphthoylamino, etc.), aC₁₋₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), aC₁₋₆ alkyl-sulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino,etc.), a C₆₋₁₄ aryl-sulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), a C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, etc.), a C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy, etc.), a C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy, etc.), a mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.),a di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy, etc.), a C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, a 5- to7-membered saturated cyclic amino which may have substituent(s), a 5- to10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl, etc.), sulpho, etc.

The “hydrocarbon group”, for example, may have one to five (preferablyone to three) of the above substituent(s) at the substitutableposition(s) and when the hydrocarbon group has two or more substituents,the respective substituents may be the same or different from eachother.

As the “C₁₋₆ alkyl which may be halogenated”, there may be mentioned,for example, a C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which mayhave one to five, preferably one to three halogen atom(s) (e.g.,fluorine, chlorine, bromine, iodine, etc.), etc. Specifically, theexamples include methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, etc.

As the “C₂₋₆ alkenyl which may be halogenated”, there may be mentioned aC₂₋₆ alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl,4-penten-1-yl, 5-hexen-1-yl) which may have one to five, preferably oneto three halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine,etc.), etc.

As the “C₂₋₆ alkynyl which may be halogenated”, there may be mentioned,for example, a C₂₋₆ alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl,5-hexyn-1-yl, etc.) which may have one to five, preferably one to threehalogen atom(s) (e.g., fluorine, chlorine, bromine, iodine, etc.), etc.

As the “C₃₋₆ cycloalkyl which may be halogenated”, there may bementioned, for example, a C₃₋₆ cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.) which may have one to five,preferably one to three halogen atom(s) (e.g., fluorine, chlorine,bromine, iodine, etc.), etc. Specifically, examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc.

As the “C₁₋₈ alkoxy which may be halogenated”, there may be mentioned,for example, a C₁₋₈ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) which may haveone to five, preferably one to three halogen atom(s) (e.g., fluorine,chlorine, bromine, iodine, etc.), etc. Specifically, examples includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.

As the “C₁₋₆ alkylthio which may be halogenated”, there may bementioned, for example, a C₁₋₆ alkylthio (e.g., methylthio, ethylthio,propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio,etc.) which may have one to five, preferably one to three halogenatom(s) (e.g., fluorine, chlorine, bromine, iodine, etc.), etc.Specifically, the examples include methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.

As the “5- to 7-membered saturated cyclic amino” in the “5- to7-membered saturated cyclic amino which may have substituent(s)”, theremay be mentioned, for example, 5- to 7-membered saturated cyclic aminoswhich may contain one or two kind(s) of and one to four hetero atom(s)selected from a nitrogen atom, a sulfur atom and an oxygen atom apartfrom one nitrogen atom and carbon atom. Specifically, the examplesinclude pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,thiomorpholino, hexahydroazepin-1-yl, etc.

As the substituent(s) in the “5- to 7-membered saturated cyclic aminowhich may have substituent(s)”, there may be mentioned, for example, oneto three of a C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), a C₆₋₁₄ aryl(e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl, etc.), a C₁₋₆ alkyl-carbonyl (e.g., acetyl,propionyl, etc.), a 5- to 10-membered aromatic heterocyclic group (e.g.,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl,3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.), oxo, etc.

In the specification, as the “C₁₋₆ alkyl group”, the “C₆₋₁₄ aryl group”and the “C₇₋₁₅ aralkyl group” in the “C₁₋₆ alkyl group which may havesubstituent(s)”, the “C₆₋₁₄ aryl group which may have substituent(s)”and the “C₇₋₁₅ aralkyl group which may have substituent(s)”, there maybe mentioned those mentioned above, respectively.

In the specification, as the “substituent(s)” in the C₁₋₆ alkyl groupwhich may have substituent(s)”, the “C₆₋₁₄ aryl group which may havesubstituent(s)” and the “C₇₋₁₅ aralkyl group which may havesubstituent(s)”, there may be mentioned those as mentioned as thesubstituent(s) in the “hydrocarbon group which may have substituent(s)”mentioned above.

The “C₁₋₆ alkyl group”, “C₆₋₁₄ aryl group” and “C₇₋₁₅ aralkyl group”,for example, may have one to five (preferably one to three) of the abovesubstituent(s) at the substitutable position(s) and when each of thesegroups has two or more substituents, the respective substituents may bethe same or different from each other.

In the specification, as the “C₁₋₆ alkyl group” and the “heterocyclicgroup” in the “heterocyclic group-C₁₋₆ alkyl group which may havesubstituent(s)”, the “heterocyclic group-sulfonyl group which may havesubstituent(s)” and the “heterocyclic group-carbonyl group which mayhave substituent(s)”, there may be mentioned the “C₁₋₆ alkyl group” andthe “heterocyclic group” as mentioned above, respectively.

As the “substituent(s)” in the “heterocyclic group C₁₋₆ alkyl groupwhich may have substituent(s)”, “heterocyclic group-sulfonyl group whichmay have substituent(s)” and “heterocyclic group-carbonyl group whichmay have substituent(s)”, there may be mentioned those as mentionedabove as substituent(s) in the “hydrocarbon group which may havesubstituent(s)”.

The “C₁₋₆ alkyl group” and the “heterocyclic group”, for example, mayhave one to five (preferably one to three) of the above substituent(s)at the substitutable position(s) and when each of these groups has twoor more substituents, the respective substituents may be the same ordifferent from each other.

In the specification, as the “C₁₋₆ alkyl group” and the “C₆₋₁₄ arylgroup” in the “C₁₋₆ alkyl group-sulfonyl group which may havesubstituent(s)”, the “C₆₋₁₄ aryl group-sulfonyl group which may havesubstituent(s)”, the “C₁₋₆ alkyl group-carbonyl group which may havesubstituent(s)” and the “C₆₋₁₄ aryl group-carbonyl group which may havesubstituent(s)”, there may be mentioned those as mentioned above for the“C₁₋₆ alkyl group” and the “C₆₋₁₄ aryl group”, respectively.

As the “substituent(s)” in the “C₁₋₆ alkyl group-sulfonyl group whichmay have substituent(s)”, the “C₆₋₁₄ aryl group-sulfonyl group which mayhave substituent(s)”, the “C₁₋₆ alkyl group-carbonyl group which mayhave substituent(s)” and the “C₆₋₁₄ aryl group-carbonyl group which mayhave substituent(s)”, there may be mentioned those as mentioned abovefor the substituent(s) in the “hydrocarbon group which may havesubstituent(s)”.

The “C₁₋₆ alkyl group” and the “C₆₋₁₄ aryl group” may have, for example,one to five (preferably one to three) of the above substituent(s) at thesubstitutable position(s) and when each of these groups has two or moresubstituents, the respective substituents may be the same or differentfrom each other.

In the present specification, as the “bivalent group in which the numberof straight-chained carbon atom(s) is 1 to 5”in the “bivalent group inwhich the number of straight-chained carbon atom(s) is 1 to 5″ which mayhave substituent(s)”, there may be mentioned, for example, astraight-chained aliphatic hydrocarbon group in which the number ofstraight-chained carbon atom(s) is 1 to 5 (e.g., a C₁₋₅ alkyl group suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, etc.; e.g., a C₁₋₅ alkenyl group such as vinyl,allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, etc.;e.g., a C₁₋₅ alkynyl group such as ethynyl, propargyl, 1-butynyl,2-butynyl, 3-butynyl, etc., etc.), etc. Among these, a C₁₋₅ alkyl groupsuch as a methyl group, an ethyl group, an n-propyl group or the like ispreferable.

As the “substituent(s)” in the “bivalent group in which the number ofstraight-chained carbon atom(s) is 1 to 5 which may havesubstituent(s)”, there may be mentioned those as mentioned above for thesubstituent(s) in the “hydrocarbon group which may have substituent(s)”.

The “bivalent group” may have one to five (preferably one to three) ofthe above substituent(s) at the substitutable position(s) and when thehydrocarbon group has two or more substituents, the respectivesubstituents may be the same or different from each other.

In the present specification, as the “substituent(s)” in the “benzylgroup which may have substituent(s)” and the “pyridylmethyl group whichmay have substituent(s)”, there may be mentioned those as mentionedabove for the substituent(s) in the “hydrocarbon group which may havesubstituent(s).

Each of the “benzyl group” and the “pyridylmethyl group” may have, forexample, one to five (preferably one to three) of the above substituentat the substitutable position(s) and when each of these groups has twoor more substituents, the respective substituents may be the same ordifferent from each other.

In the specification, as the “heterocyclic group” in the “heterocyclicgroup which may have substituent(s)”, there may be mentioned, forexample, a monovalent group formed by removing a hydrogen atom from a 5-to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic ringcontaining one or two kind(s) and one to four (preferably one to three)hetero atom(s) optionally selected from a nitrogen atom, a sulfur atomand an oxygen atom apart from the carbon atom(s), preferably, (1) 5- to14-membered (preferably 5- to 10-membered) aromatic heterocyclic ring,(2) 5- to 10-membered non-aromatic heterocyclic ring or (3) 7-to10-membered bridged heterocyclic ring.

As the “5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle”, there may be mentioned, for example, aromatic heterocyclessuch as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole,benzoxazole, benzothiazole, benzisothiazole, naphto[2,3-b]thiophene,furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indol, isoindol, 1H-indazole, purine, 4H-quinolizine,isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,quinzoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine,phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan,phenoxazine, etc. or rings formed by condensing the above heterocycle(preferably monocycle) with one or more (preferably one or two) aromaticring(s) (e.g., a benzene ring, etc.), etc.

As the “5- to 10-membered non-aromatic heterocyclic ring”, there may bementioned, for example, pyrrolidine, imidazoline, pyrazolidine,pyrazoline, piperidine, piperazine, morpholine, thiomorpholine,dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole,dithiazole, etc.

As the “7- to 10-membered bridged heterocyclic ring”, there may bementioned, for example, quinuclidine, 7-azabicyclo[2.2.1]heptane, etc.

The “heterocyclic group” preferably is a 5- to 14-membered (preferably5- to 10-membered) (monocyclic or bicyclic) heterocyclic groupcontaining one or two kind(s) and preferably one to four hetero atom(s)selected from a nitrogen atom, a sulfur atom and an oxygen atom.Specifically, examples include a aromatic heterocyclic group such as2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl,2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl,3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl, etc., a non-aromatic heterocyclicgroup such as 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl,4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl,1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino, etc., and thelike.

Among these, for example, a 5- or 6-membered heterocyclic groupcontaining one to three hetero atom(s) selected from a nitrogen atom, asulfur atom and an oxygen atom apart from the carbon atom(s), etc., arepreferable.

Specifically, the examples include 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl,3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl,2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,morpholino, thiomorpholino, etc.

As the “substituent(s)” in the “heterocyclic group which may havesubstituent(s)”, there may be mentioned those similar to thesubstituent(s) in the “hydrocarbon group which may have substituent(s)”mentioned above.

The “heterocyclic group” may have, for example, one to five (preferablyone to three) of the above substituent(s) at the substitutableposition(s) and when the hydrocarbon group has two or more substituents,each substituent may be the same or different from each other.

In the present specification, as an acyl group, there may be mentioned,for example, a group represented by the formula: —COOR⁶¹, —CONR⁷¹R⁸¹,—COR⁹¹, —COOR⁶², —CONR⁷²R⁸², —COR⁹², —COOR⁶⁴, —CONR⁷⁴R⁸⁴, —COR⁹⁴,—COOR^(6′1), —CONR^(7′1)R^(8′1), —COR^(9″1), —COOR^(6′1′),—CONR^(7′1′)R^(8′1′), —COR^(9″1′), —COOR^(6″1″), —COOR^(6′1b),—COR^(9′3b), —(C═S)—NR¹⁰R¹¹, —SO₂—R¹²³ or —SO₂—R^(12′3b) (wherein R⁶¹,R⁷¹, R⁸¹, R⁹¹, R⁶², R⁷², R⁸², R⁹², R⁶⁴, R⁷⁴, R⁸⁴, R⁹⁴, R^(6′1), R^(7′1),R^(8′1), R^(9″1), R^(6′1′), R^(7′1′), R^(8′1′), R^(9″1′), R^(6″1″),R^(6′1b), R^(9′3b), R¹²³ and R^(12′3b) have the meanings given above,R¹⁰ and R¹¹ are the same or different, and may be a hydrogen atom, ahydrocarbon group which may have the substituent(s) mentioned above or aheterocyclic group which may have the substituent(s) mentioned above,and R¹⁰ and R¹¹, taken together with a neighboring nitrogen atom, mayform a cyclic group which may have substituent(s)). Specifically,examples include, a lower (C₁₋₆)alkanoyl group (e.g., formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,etc.), a lower (C₃₋₇)alkenoyl group (e.g., acryloyl, methacryloyl,crotonoyl, isocrotonoyl, etc.), a C₄₋₇ cycloalkanecarbonyl group (e.g.,cyclopropanecarbonyl group, cyclobutanecarbonyl group,cyclopentanecarbonyl group, cyclohexanecarbonyl group, etc.), a lower(C₁₋₄)alkane sulfonyl group (e.g., mesyl, ethanesulfonyl,propanesulfonyl, etc.), a C₇₋₁₄ aroyl group (e.g., benzoyl, p-toluoyl,1-naphthoyl, 2-naphthoyl, etc.), a C₆₋₁₀ aryl lower (C₂₋₄)alkanoyl group(e.g., phenylacetyl, phenylpropionyl, hydroatropoyl, phenylbutyryl,etc.), a C₆₋₁₀ aryl lower (C₃₋₅)alkenoyl group (e.g., cinnamoyl,atropoyl, etc.), a C₆₋₁₀ arenesulfonyl group. (e.g., benzenesulfonyl,p-toluenesulfonyl group, etc.), etc.

In the present specification, as the “cyclic group” in the “cyclic groupwhich may have substituent(s)”, there may be mentioned, for example, acyclic hydrocarbon group or a heterocyclic group.

As the “cyclic hydrocarbon group”, a cyclic hydrocarbon group having 1to 16 carbon atom(s), etc., are preferable, and a cycloalkyl group andan aryl group, etc. may be used.

As the “cycloalkyl group”, for example, a C₃₋₆ cycloalkyl group (forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), etc.,are preferable.

As the “aryl group”, for example, a C₆₋₁₄ aryl group (for example,phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl, etc.), etc., are preferable.

As the heterocyclic group, those as mentioned above may be used.

As the “substituent(s)” in the “cyclic group which may havesubstituent(s)”, there maybe mentioned those as mentioned above for thesubstituent(s) in the “hydrocarbon group which may have substituent(s)”.

The “cyclic group”, for example, may have one to five (preferably one tothree) of the above substituent(s) at the substitutable position(s) andwhen the hydrocarbon group has two or more substituents, the respectivesubstituents may be the same or different from each other.

In the present specification, as the group that is bonded through thecarbon atom, there may be used a cyano group, the hydrocarbon groupwhich may have substituent(s) mentioned above, an acyl group mentionedabove, a heterocyclic group which may have substituent(s), which isformed by removing a hydrogen atom substituted on a carbon atom from theheterocyclic ring which may have substituent(s) mentioned above; etc.

In the specification, as the “group that is bonded through the nitrogenatom”, there may be used, for example, an amino group which may havesubstituent(s), a heterocyclic group which may have substituent(s)formed by removing a hydrogen atom present on a nitrogen atom from theheterocyclic group which may have substituent(s) mentioned above.

As the “amino group which may have substituent(s)”, (1) an amino groupwhich may have one or two substituent(s) and (2) a cyclic amino groupwhich may have substituent(s) may be used.

As the “substituent” in the “(1) amino group which may have one or twosubstituent(s)”, there maybe used, for example, a hydrocarbon groupwhich may have substituent(s) mentioned above, a heterocyclic groupwhich may have substituent(s) mentioned above, an acyl group mentionedabove, an alkylydene group which may have substituent(s); etc.

As the “alkylydene group” in the “alkylydene group which may havesubstituent(s)”, there may be used, for example, a C₁₋₆ alkylydene group(for example, methylidene, ethylidene, propylidene, etc.), etc.

As the “substituent(s)” in the “alkylidene group which may havesubstituent(s)”, there may be mentioned those similar to thesubstituent(s) in the “hydrocarbon group which may have substituent(s)”mentioned above. The number of the substituent(s) is usually one tofive, preferably one to three.

When the number of the “substituent(s)” in the “amino group which mayhave one or two substituent(s)” is two, the two substituents may be thesame or different from each other.

As the “cyclic amino group” in the “cyclic amino group which may havesubstituent(s)” in the above (2), there may be used, for example, a 5-to 7-membered non-aromatic cyclic amino group which may contain one ortwo kind(s) and one to four hetero atom(s) selected from-a nitrogenatom, a sulfur atom and an oxygen atom apart from the nitrogen atom andcarbon atom(s); etc., and specifically, pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl,imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl,tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl,3,4-dihydro-1(2H)-pyrimidinyl, etc. may be used.

As the “substituent(s)” in the “cyclic amino group which may havesubstituent(s)”, there may be mentioned, for example, those similar tothe substituent(s) in the “5- to 7-membered saturated cyclic amino groupwhich may have substituent(s)” mentioned above as the “substituent(s)”in the “hydrocarbon group which may have substituent(s)”. The number ofthe substituent is one to three.

As specific examples of the 5- to 7-membered non-aromatic cyclic aminogroup having an oxo group, there may be used 2-oxo imidazolidin-1-yl,2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-pyrimidinyl,2-oxo-3,6-dihydro-1(2H)-pyrimidinyl,2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl,2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl,2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl, etc.

In the present specification, as the “group that is bonded through theoxygen atom”, there may be used, for example, a group represented by theformula: —OR¹³¹, —OR¹³² or —OR³⁴ (wherein R¹³¹, R¹³² and R¹³⁴ have themeanings given above), etc.

In the present specification, as the “group that is bonded through thesulfur atom”, there may be used, for example, a group represented by theformula: —SR¹⁴ (wherein R¹⁴ is a hydrogen atom or a hydrocarbon groupwhich may have substituent(s) mentioned above), a group represented bythe formula: —SO—R¹⁵ (wherein R¹⁵ is a hydrogen atom or a hydrocarbongroup which may have substituent(s) mentioned above), a grouprepresented by the formula: —SO₂—R¹²³ (wherein R¹²³ is a hydrogen atomor a hydrocarbon group which may have substituent(s) mentioned above), agroup represented by the formula: —SO₂—R^(12′3b) (wherein R^(12′3b) hasthe meaning given above) and a sulfur-containing heterocyclic groupwhich may have substituent(s) formed by removing a hydrogen atomsubstituted on a sulfur atom from a sulfur-containing heterocycle whichmay have substituent(s).

In the specification, as the “sulfur-containing heterocyclic group” inthe “sulfur-containing heterocyclic group which may havesubstituent(s)”, there may be mentioned, for example, a monovalent groupformed by removing an optional hydrogen atom from a 5- to 14-membered(monocyclic, bicyclic or tricyclic) sulfur-containing heterocyclecontaining one or two kind(s) of and one to four (preferably one tothree) hetero atom(s) selected from a nitrogen atom, a sulfur atom andan oxygen atom apart from the carbon atom(s) and sulfur atom,preferably, (1) 5- to 14-membered (preferably 5- to 10-membered)aromatic heterocyclic group or (2) 5- to 10-membered non-aromaticsulfur-containing heterocyclic group.

As the “5- to 14-membered (preferably 5- to 10-membered) aromaticsulfur-containing heterocycle, there may be mentioned, for example, anaromatic sulfur-containing heterocycle such as thiophene,benzo[b]thiophene, naphto[2,3-b]thiophene, thiazole, isothiazole, etc.,a ring formed by condensing the above ring (preferably monocycle) withone or more (preferably one or two) of an aromatic ring(s) (e.g.,benzene ring, etc.); etc.

As the “5- to 10-membered aromatic sulfur-containing heterocyclic ring”,there may be mentioned, for example, thiomorpholine, thiadiazole,dithiazole, etc.

As the “substituent(s)” in the “sulfur-containing heterocyclic groupwhich may have substituent(s)”, there may be mentioned those similar tothe substituent(s) in the “hydrocarbon group which may havesubstituent(s)” as mentioned above.

The “sulfur-containing heterocyclic group”, for example, may have one tofive (preferably one to three) of the above substituent(s) at thesubstitutable position(s) and when the hydrocarbon group has two or moresubstituents, the respective substituents may be the same or differentfrom each other.

In the present specification, as the “aromatic group” in the “aromaticgroup which may have substituent(s)”, for example, an aromatichydrocarbon group or an aromatic heterocyclic group may be used.

As the aromatic hydrocarbon group, an aromatic hydrocarbon group having1 to 16 carbon atom(s), etc. is preferable, and specifically an arylgroup may be used.

As the “aryl group”, for example, a C₆₋₁₄ aryl group (for example,phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl, etc.), etc., are preferable.

As the “aromatic heterocyclic group”, there may be mentioned, forexample, a monovalent group formed by removing an optional hydrogen atomfrom a 5- to 14-membered (monocyclic, bicyclic or tricyclic) aromaticheterocyclic ring containing one or two kind(s) and one to four(preferably one to three) hetero atom(s) selected from a nitrogen atom,a sulfur atom and an oxygen atom apart from the carbon atom(s),preferably, (1) 5- to 14-membered (preferably 5- to 10-membered)aromatic heterocyclic ring or (2) 7- to 10-membered heterocyclic bridgedring.

As the “5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle”, there may be mentioned, for example, an aromaticheterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan,benzimidazole, benzoxazole, benzothiazole, benzisothiazole,naphto[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indol, isoindol, 1H-indazole, purine,4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinzoline, cinnoline, carbazole, β-carboline,phenanthridine, acridine, phenazine, thiazole, isothiazole,phenothiazine, isoxazole, furazan, phenoxazine, etc. or a ring formed bycondensing the above ring (preferably monocycle) with one or more(preferably one or two) of an aromatic ring(s) (e.g., benzene ring,etc.); etc.

As the “7- to 10-membered heterocyclic bridged ring”, there may be used,for example, quinuclidine, 7-azabicyclo[2.2. 1]heptane, etc.

The “aromatic heterocyclic group” preferably is a 5- to 14-membered(preferably 5- to 10-membered) (monocyclic or bicyclic) aromaticheterocyclic group containing one or two kind(s) and preferably one tofour hetero atom(s) selected from a nitrogen atom, a sulfur atom and anoxygen atom apart from the carbon atom(s). Specifically, there may beused, for example, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl,3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl,3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.

Among these, for example, 5- or 6-membered aromatic heterocyclic groupcontaining one to five hetero atom(s) selected from a nitrogen atom, asulfur atom and an oxygen atom apart from the carbon atom(s), etc., aremore preferable. Specifically, there may be mentioned 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl,2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl,4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, etc.

As the “substituent(s)” in the “heterocyclic group which may havesubstituent(s)”, there may be mentioned those similar to thesubstituent(s) in the “hydrocarbon group which may have substituent(s)”mentioned above.

The “aromatic group” may have one to five (preferably one to three) ofthe above substituent(s) at the substitutable position(s) and when thehydrocarbon group has two or more substituents, the respectivesubstituents may be the same or different from each other.

As the “substituent(s)” of the ring A and the ring B, there may bementioned those similar to the substituent(s) in the “hydrocarbon groupwhich may have substituent(s)” as mentioned above.

R¹ is a hydrogen atom, a group that is bonded through the carbon atom, agroup that is bonded through the nitrogen atom, a group that is bondedthrough the oxygen atom or a group that is bonded through the sulfuratom.

As R¹, a hydrogen atom, a hydrocarbon group which may havesubstituent(s), an acyl group, a heterocyclic group which may havesubstituent(s) or a group that is bonded through the oxygen atom, etc.,are preferable. Among these, a hydrogen atom, a hydrocarbon group whichmay have substituent(s), a group represented by the formula: —COOR⁶¹(wherein R⁶¹ has the meaning given above), a group represented by theformula: —CONR⁷¹R⁸¹ (wherein R⁶¹ and R⁷¹ have the meanings given above),a group represented by the formula: —COR⁹¹ (wherein R⁹¹ has the meaninggiven above) or a group represented by the formula: —OR¹³¹ (wherein R¹³¹has the meaning given above), etc., are preferable. Particularly, as R¹,a group represented by the formula: —COOR⁶¹ (wherein R⁶¹ is ahydrocarbon group which may have substituent(s)) is preferable. As R⁶¹,a C₁₋₆ alkyl group such as methyl, ethyl, propyl, n-butyl, tert-butyl,etc. is preferable.

R² is a hydrogen atom, a group that is bonded through the carbon atom, agroup that is bonded through the nitrogen atom, a group that is bondedthrough the oxygen atom or a group that is bonded through the sulfuratom.

As R², a hydrogen atom, a hydrocarbon group which may havesubstituent(s), a group represented by the formula: —COOR⁶² (wherein R⁶²is a hydrocarbon group which may have substituent(s)), a grouprepresented by the formula: —CONR⁷²R⁸² (wherein R⁷² and R⁸² have themeanings given above), a group represented by the formula: —COR⁹²(wherein R⁹² has the meaning given above) and a group represented by theformula: —OR¹³² (wherein R¹³² has the meaning given above) arepreferable. Among these, a hydrocarbon group which may havesubstituent(s) is more preferable, and in particular a C₁₋₆ alkyl group(e.g., methyl, ethyl or the like) is even more preferable. R³ is ahydrogen atom, a hydrocarbon group which may have substituent(s), anacyl group, a heterocyclic group which may have substituent(s) or agroup represented by the formula: —SO₂—R¹²³ (wherein R¹²³ has themeaning given above).

As R³, a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, n-butyl, etc.)which may have substituent(s) (e.g., hydroxy), a C₇₋₁₅ aralkyl group(e.g., benzyl, phenylethyl, etc.) which may have substituent(s), a grouprepresented by the formula: —COR^(9′3) (wherein R^(9′3) is a C₁₋₆ alkylgroup which may have substituent(s) or a C₇₋₁₅ aralkyl group (e.g.,benzyl, phenylethyl, etc.) which may have substituent(s)) and a grouprepresented by the formula: —SO₂—R^(12′3) (wherein R^(12′3) is a C₁₋₆alkyl group (e.g., methyl, ethyl, etc.) which may have substituent(s) ora C₇₋₁₅ aralkyl group (e.g., benzyl, phenylethyl, etc.) which may havesubstituent(s)); are preferable, particularly a C₁₋₆ alkyl group (e.g.,methyl, ethyl, propyl, n-butyl, etc.) which may have substituent(s), aC₇₋₁₅ aralkyl group (e.g., benzyl, phenylethyl, etc.) which may havesubstituent(s), a C₁₋₆ alkyl-sulfonyl group (e.g., methylsulfonyl, etc.)which may have substituent(s) and a C₆₋₁₄ aryl-carbonyl group (e.g.,benzoyl, etc.) are more preferable.

As R³, a benzyl group which may have substituent(s) and a heterocyclicgroup-ethyl group which may have substituent(s) are still morepreferable, and a heterocyclic ring ethyl group which may havesubstituent(s) is the most preferable.

R⁴ is a hydrogen atom, a group that is bonded through the carbon atom, agroup that is bonded through the nitrogen atom, a group that is bondedthrough the oxygen atom or a group that is bonded through the sulfuratom.

As R⁴, a hydrogen atom, a hydrocarbon group which may havesubstituent(s), a group represented by the formula: —COOR⁶⁴ (wherein R⁶⁴has the meaning given above), a group represented by the formula:—CONR⁷⁴R⁸⁴ (wherein R⁷⁴ and R⁸⁴ have the meanings given above), a grouprepresented by the formula: —COR⁹⁴ (wherein R⁹⁴ has the meaning givenabove), and a group represented by the formula: —OR¹³⁴ (wherein R¹³⁴ hasthe meaning given above), etc., are preferable, and particularly aC₁₋₆alkyl group (e.g., methyl, ethyl, or the like ) which may havesubstituent(s) is more preferable.

R⁵ is a cyclic group which may have substituent(s).

As R^(5,) a cyclic hydrocarbon group which may have substituent(s) ispreferable, and particularly an aryl group (e.g., phenyl and the like)such as a C₆₋₁₄ aryl group which may have substituent(s) (e.g., nitro,cyano, formyl, etc.), etc., are more preferable. Among the substitutablepositions on phenyl group, para position is preferable while there areno restrictions.

As the compound (I) of the present invention, the following compounds(A) to (E) are preferably used.

[Compound (A)]

-   Compound (I) wherein R¹ is a C₁₋₆ alkyl group which may have    hydroxy, a group represented by the formula: —COOR^(6′1) (wherein    R^(6′1) is a C₁₋₆ alkyl group), a group represented by the formula:    —CONR^(7′1)R^(8′1) (wherein R^(7′1) and R^(8′1) are each a hydrogen    atom, a C₁₋₆ alkyl group or a C₆₋₁₀ aryl group, and R^(7′1) and    R^(8′1) are taken together to form a cyclic group which may have    substituent(s)) or a group represented by the formula: —COR^(9″1)    (wherein R^(9″1) is a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group or a    heterocyclic group which may have substituent(s)); R² and R⁴ are    each a hydrogen atom or a C₁₋₆ alkyl group; R³ is a hydrogen atom or    a hydrocarbon group which may have substituent(s) or a heterocyclic    group which may have substituent(s); and R⁵ is an aryl group which    may have substituent(s), a C₃₋₈ cycloalkyl group which may have    substituent(s) or a heterocyclic group which may have    substituent(s).

[Compound (B)]

-   Compound (I) wherein R¹ is a group represented by the formula:    —COOR^(6′1) (wherein R^(6′1) is a C₁₋₆ alkyl group); R² is a C₁₋₆    alkyl group which may have substituent(s); R³ is a C₁₋₆ alkyl group    which may have substituent(s), a C₇₋₁₅ aralkyl group which may have    substituent(s), a C₁₋₆ alkyl-sulfonyl group which may have    substituent(s) or a C₆₋₁₄ aryl-carbonyl group which may have    substituent(s); R⁴ is a C₁₋₆ alkyl group which may have    substituent(s); and R⁵ a C₆₋₁₄ aryl group which may have    substituent(s).

[Compound (C)]

-   Compound (I) wherein R¹ is a group represented by the formula:    —COOR^(6′1) (wherein R^(6′1) is a C₁₋₆ alkyl); R² is a C₁₋₆ alkyl    group; R³ is a C₁₋₆ alkyl group which may have hydroxy(s), a C₇₋₁₅    aralkyl group, a C₁₋₆ alkyl-sulfonyl group or a C₆₋₁₄ aryl-carbonyl    group; R⁴ is a C₁₋₆ alkyl group; R⁵ is a C₆₋₁₄ aryl which may have    nitro, cyano or a C₁₋₃ acyl group.

[Compound (D)]

-   Compound represented by the formula:    [wherein R¹ is a C₁₋₆ alkyl group, a group represented by the    formula: —COOR^(6′1′) (wherein R^(6′1′) is a C₁₋₆ alkyl group), a    group represented by the formula: —CONR^(7′1′)R^(8′1′) (wherein    R^(7′1′) and R^(8′1′) are each a hydrogen atom, a C₁₋₆ alkyl group    or a C₆₋₁₀ aryl group), a group represented by the formula:    —C(OH)R^(161′)R^(16′1′) (wherein R^(161′) and R^(16′1′) are each a    hydrogen atom or a C₁₋₆ alkyl group), a group represented by the    formula: —COR^(9″1′) (wherein R^(9″1′) is a C₁₋₆ alkyl group, a C₃₋₈    cycloalkyl group or a heterocyclic group which may have    substituent(s)); R¹⁷ is a C₆₋₁₄ aryl group which may have    substituent(s) or a heterocyclic group which may have    substituent(s);. R¹⁸ is a nitro group, a C₁₋₆ alkyl group which may    have substituent(s), a halogen atom, a C₁₋₆ alkoxy group, a cyano    group, a carboxyl group, a carboxylic acid ester group, a hydroxy    group or an amido group; n is an integer from one to three].

[Compound (E)]

-   Compound represented by the formula:    [(wherein R¹⁹ is a C₆₋₁₄ aryl group (e.g., phenyl) which may have    substituent(s) or a heterocyclic group which may have    substituent(s); one of R²⁰ and R²¹ is a nitro group or a cyano    group; ring A may further have substituent(s) (e.g., a C₁₋₆ alkyl, a    halogen atom (e.g., chlorine), nitro, cyano, formyl); and n is an    integer from one to three].

Specifically, as the compound (I) of the present invention, compoundsdescribed in Example 1 to 251 shown below are preferable. Amongthese, 1) ethyl1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate, 2)methyl 1-benzyl-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate,3) methyl1-benzyl-4-(4-formylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate, 4)methyl 4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole-3-carboxylate or salt thereof, 5)4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole-3-carbonitrile or salt thereof, 6)4-(4-cyanophenyl)-2,5-dimethyl-1-((6-methyl-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrileor salt thereof, and 7)4-(4-cyanophenyl)-2,5-dimethyl-1-((6-chloro-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrileor salt thereof, etc., are more preferable.

Among the compound (I) of the present invention, (1) a compoundrepresented by the formula:

[wherein R^(1a) is a hydrogen atom, a group that is bonded through thecarbon atom, a group that is bonded through the nitrogen atom, a groupthat is bonded through the oxygen atom or a group that is bonded throughthe sulfur atom; R^(2a) is a hydrogen atom, a group that is bondedthrough the carbon atom, a group that is bonded through the nitrogenatom, a group that is bonded through the oxygen atom or a group that isbonded through the sulfur atom; R^(3a) is an aromatic group which mayhave substituent(s); R^(4a) is a hydrogen atom, a group that is bondedthrough the carbon atom, a group that is bonded through the nitrogenatom, a group that is bonded through the oxygen atom or a group that isbonded through the sulfur atom; at least one of R^(5a) and R^(5aa) is anitro group, a cyano group or a formyl group; ring B may further havesubstituent(s); and X³ is a bivalent group in which the number ofstraight-chained carbon atoms is 1 to 5 which may have substituent(s)](provided that (1) ethyl4-(3-cyanophenyl)-1-(2-naphthylmethyl)-1H-pyrrole-3-carboxylate, (2)ethyl 4-(3-cyanophenyl)-1-(1-naphthylmethyl)-1H-pyrrole-3-carboxylate,(3) 1-benzyl-3-(3-nitrophenyl)-1H-pyrrole, (4)1-benzyl-3-methyl-4-(4-nitrophenyl)-1H-pyrrole, (5) tert-butyl4-ethyl-1-(4-nitrobenzyl)-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate,(6) tert-butyl4-ethyl-1-(4-methoxybenzyl)-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate,(7) tert-butyl1-benzyl-4-ethyl-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate, (8)tert-butyl 1-benzyl-4-methyl-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate,(9) methyl [4-(aminocarbonyl)-5-methyl-3-(4-nitrophenyl)-1-(2-pyridin-2-ylethyl)-1H-pyrrol-2-yl] acetate, (10)1-benzyl-N-{2′-[(tert-butylamino)sulfonyl]-1,1′-biphenyl-4-yl}-4-(3-cyanophenyl)-1H-pyrrole-3-carboxamide,(11)3-{1-[(E)-1-cyano-2-(3,5-dichloro-1-methyl-1H-pyrazol-4-yl)-2-hydroxyethenyl]-1H-pyrrol-3-yl}benzonitrile,(12) methyl 4-(4-amino-3-nitrophenyl)-1-benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylate, (13) methyl1-benzoyl-4-(3-nitrophenyl)-1H-pyrrole-3-carboxylate, (14)4-[1-benzyl-2-(2-furanyl)-5-phenyl-1H-pyrrol-3-yl]-benzonitrile and (15)4-[1-benzyl-2,5-diphenyl-1H-pyrrol-3-yl]-benzonitrile are excluded), asalt thereof or a prodrug thereof; or (2) compound represented by theformula:

[wherein R^(1b) is a cyano group or a group represented by the formula:—COOR^(6′1b) (wherein R^(6′1b) is a C₁₋₆ alkyl group); R^(2b) is ahydrogen atom or a C₁₋₆ alkyl group; R^(3b) is a C₁₋₆ alkyl group whichmay have substituent(s), a C₇₋₁₅ aralkyl group which may havesubstituent(s), a 5- to 14-membered aromatic heterocyclic group-C₁₋₆alkyl group which may have substituent(s), a group represented by theformula: —CO—R^(9′3b) (wherein R^(9′3b) is a C₁₋₆ alkyl group which mayhave substituent(s), a C₆₋₁₄ aryl group which may have substituent(s) ora 5- to 14-membered aromatic heterocyclic group which may havesubstituent(s)) or a group represented by the formula: —SO₂—R^(12′3b)(wherein R^(12′3b) is a C₁₋₆ alkyl group which may have substituent(s),a C₆₋₁₄ aryl group which may have substituent(s) or a 5- to 14-memberedaromatic heterocyclic group which may have substituent(s)); R^(4b) is ahydrogen atom or a C₁₋₆ alkyl group; and at least one of R^(5b) andR^(5bb) is a nitro group, a cyano group or a formyl group] (providedthat (1) ethyl4-(3-cyanophenyl)-1-(2-naphthylmethyl)-1H-pyrrole-3-carboxylate, (2)ethyl 4-(3-cyanophenyl)-1-(1-naphthylmethyl)-1H-pyrrole-3-carboxylate,(3) methyl 4-(4-amino-3-nitrophenyl)-1-benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylate, (4) methyl4-(4-amino-3-nitrophenyl)-1-butyl-2,5-dimethyl-1H-pyrrole-3-carboxylate,(5) methyl4-(4-amino-3-nitrophenyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate, (6)methyl 1-benzoyl-4-(3-nitrophenyl)-1H-pyrrole-3-carboxylate and (7)dimethyl 4-(3-nitrophenyl)-1H-pyrrole-1,3-dicarboxylate are excluded), asalt thereof or prodrug thereof, are novel compounds.

In the above formula (I′), as R^(1a), a group represented by theformula: —COOR^(6′1a) (wherein R^(6′1a) is a C₁₋₆ alkyl group) ispreferable. As R^(6′1a), methyl, ethyl, propyl, n-butyl, tert-butyl,etc., are preferable and particularly methyl and ethyl are morepreferable.

As R^(2a), a C₁₋₆ alkyl group such as methyl, ethyl, etc., is preferableand particularly methyl is more preferable.

As R^(3a), a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, butyl or thelike) which may have substituent(s) such as hydroxy, a C₇₋₁₅ aralkylgroup (e.g., benzyl, phenylethyl, etc.) which may have substituent(s), agroup represented by the formula: —COR^(9″′3a) (wherein R^(9″′3a) is aC₁₋₆ alkyl group (e.g., methyl, ethyl or the like) which may havesubstituent(s), or a C₆₋₁₄ aryl group (e.g., phenyl or the like) whichmay have substituent(s)), a group represented by the formula:—S₂—R^(12′3a) (wherein R^(12′3a) is a C₁₋₆ alkyl group (e.g., methyl,ethyl or the like) which may have substituent(s) or a C₆₋₁₄ aryl group(e.g., phenyl or the like) which may have substituent(s)), etc., ispreferable. Among these, methyl, ethyl, propyl, n-butyl, hydroxybutyl,methylsulfonyl, benzoyl, phenylsulfonyl, benzyl, phenylethyl, etc., aremore preferable, and particularly, benzyl is even more preferable.

As R^(4a), a C₁₋₆ alkyl group such as methyl, ethyl, etc. is preferable,and methyl is more preferable.

It is preferable that one of R^(5a) and R^(5aa) is a nitro group, cyanogroup or a formyl group, and the other is a hydrogen atom, a C₁₋₆ alkylgroup (e.g., methyl, ethyl, etc.), a halogen atom (e.g., fluorine,chlorine, bromine, iodine, etc., and more preferably chlorine), nitrogroup, a cyano group or a formyl group or the ring B has a hydrogenatom, a C₁₋₆ alkyl group (e.g., methyl, ethyl, etc.), a halogen atom(e.g., fluorine, chlorine, bromine, iodine, etc., and more preferablychlorine), nitro group, a cyano group or a formyl group at asubstitutable position.

By m, an integer from one to five, preferably one or two, mostpreferably one, is denoted.

In the above formula (I″), as a C₁₋₆ alkyl group represented byR^(6′1b), methyl, ethyl, propyl, n-butyl, tert-butyl, etc., arepreferable, and particularly methyl and ethyl are more preferable.

As the C₁₋₆ alkyl group represented by R^(2b), methyl and ethyl, etc.,are preferable, and particularly methyl is more preferable.

As the cyclic group which may have substituent(s) represented by R^(3b),a C₆₋₁₄ aryl group (e.g., phenyl, etc.) which may have substituent(s),etc., are preferable.

As a C₁₋₆ alkyl group represented by R^(4b), methyl, ethyl, etc., arepreferable, and particularly methyl is more preferable.

As R^(5b), a nitro group is preferable.

Specifically, as the compound (I′) or (I″), compounds produced inExamples 1 to 251 shown below, or salt thereof are preferable, and amongthese 1) ethyl1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate, 2)methyl 1-benzyl-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate,3) methyl1-benzyl-4-(4-formylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate, 4)methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole-3-carboxylateor salt thereof, 5)4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole-3-carbonitrileor salt thereof, 6)4-(4-cyanophenyl)-2,5-dimethyl-1-((6-methyl-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrile or salt thereof and 7)4-(4-cyanophenyl)-2,5-dimethyl-1-((6-chloro-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrile or salt thereof, etc., are preferable.

As the salt of the compound (I) including compound (I′) or (I″) of thepresent invention, there may be mentioned, for example, a metal salt, anammonium salt, a salt with an organic base, a salt with an inorganicacid, a salt with an organic acid, a salt with a basic or acidic aminoacid, etc. Preferable examples of the metal salt include an alkali metalsalt such as sodium salt, potassium salt, etc.; an alkaline earth metalsalt such as calcium salt, magnesium salt, barium salt, etc.; aluminumsalt; etc. Preferable examples of the salt with an organic base includea salt with trimethylamine, triethylamine, pyridine, picoline,2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, etc.Preferable examples of the salt with an inorganic acid include a saltwith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc. Preferable examples of the salt with an organicacid include a salt with formic acid, acetic acid, trifluoroacetic acid,phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, etc.

Preferable examples of the salt with a basic amino acid include a saltwith arginine, lysine, ornithine, etc. Preferable examples of the saltwith an acidic amino acid include a salt with aspartic acid, glutamicacid, etc.

Among these, a pharmaceutically acceptable salt is preferable. Forexample, when compound has acidic functional group(s), an inorganic saltsuch as an alkali matal salt (e.g., sodium salt, potassium salt, etc.),an alkaline earth metal salt (e.g., calcium salt, magnesium salt, bariumsalt, etc.), an ammonium salt, etc., are preferable, and when compoundhas basic functional group(s), a salt with an inorganic acid such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc. or a salt with an organic acid acetic acid,phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonicacid, etc., preferable.

The compound (I) or salt thereof, including compounds (I′) and (I″), ofthe present invention, can be obtained by the method shown in thereaction scheme 1 shown below or a method similar to the method or canalso be obtained by a known method or a method similar thereto. Somecompounds included in the formula (I) can be obtained by converting thefunctional groups of the other compounds (Compounds (I), (II), (III),etc.) obtained in accordance with the reaction shown in the followingreaction scheme 1, by a per se known method or a similar method thereto(e.g., oxidation, reduction, hydrolysis, acylation, alkylation,amidation, amination, transfer reaction, etc.).

In the reaction scheme 1, while the respective symbols have the samemeanings as those given above, the functional group(s) may be protectedby a protective group and the like which is conventionally used in thefield of organic synthesis, if necessary. X is a halogen atom. In thereaction scheme, each compound also includes a salt thereof, and as thesalt, there may be mentioned the same salts as those of the compound(I).

In the reaction scheme 1, as the compounds (II), (III), (IV), (V), (VI)and (VII), if these compounds are available in the market, thoseavailable in the market may be used as they are, while these compoundscan be produced by per se known methods or by manners similar to knownmethods.

The compound (II) can be obtained, for example, by subjecting thecompound (III) to Suzuki reaction or a reaction similar thereto. Thecompound (II) can also be obtained by a method described in literatures(Boberg et al., Liebigs. Ann. Chem. 1985, pp 239-250; Meyer et al.,Liebigs. Ann. Chem. 1981, pp 1534-1544; Sanchez et al., J. Chem. Soc.,Perkin I, Vol 2, 1982, pp 441-447; Barton et al., J. Chem. Soc., Chem.Commun. 1985, pp 1098-1100; Joule et al., Chapman & Hall, HeterocyclicChemistry; Jones et al., John Wiley & Sons; Pyrroles: Part One: TheSynthesis and the Physical and Chemical Aspects of the Pyrrole Ring (TheChemistry of Heterocyclic Compounds, Vol. 48, Part One) or by a methodsimilar to these methods.

The compound (III) can be obtained, for example, by a method describedin literatures (Baxter et al., J. Med. Chem. 1993, Vol. 36, pp 239-250;Petruso et al., J. Heterocyclic Chem. 1990, Vol. 27, pp 1209-1211) or bya method similar to these methods.

[Process A]

The compound (I) or (IV) can be synthesized by reacting the compound(III) or (III) with an alkyl halide, an acyl halide, a sulfonyl halide,etc., in the presence of a base. The reaction can be carried out in aconventional manner.

As the halogen atom, there may be mentioned, for example, fluorine atom,chlorine atom, bromine atom, iodine atom, etc.

As the base, there maybe mentioned, for example, an alkali metal hydridesuch as sodium hydride, potassium hydride, etc., alkali metal amide suchas sodium amide, etc.

The amount of the base used is about 1.0 mol to about 10 mol (preferablyabout 1.0 mol to about 2.0 mol) per mol of the compound (II) or (III).

The amount of the alkyl halide, acyl halide, sulfonyl halide, etc., usedis about 1.0 mol to about 10 mol (preferably about 1.0 mol to about 2.0mol) per mol of the compound (II) or (III).

Reaction temperature is about −70 to about 100° C., preferably about 0to about 50° C. Reaction time is about 5 minutes to about 20 hours.

The reaction of the present invention is usually carried out in asolvent which does not interfere with the reaction. As the solvent whichdoes not interfere with the reaction, there maybe used, for example, anether such as diethylether, dioxane, tetrahydrofuran (THF), etc.; asaturated hydrocarbon such as hexane, pentane, etc.; a halogenatedhydrocarbon such as dichloromethane, chloroform, etc.; an amide such asN,N-dimethylfromamide, etc.; an aromatic hydrocarbon such as benzene,toluene, etc. Single solvent or a mixed solvent consisting of two ormore of these solvents in a conventional ratio, may be used.

When the alkyl halide, acyl halide or sulfonyl halide used is protectedby a protective group, the protective group can be removed by a knownmethod or by a method similar to a known method to produce the compound(I). For example, when 2-(4-iodobutoxy)tetrahydropyran is used as analkyl halide, tetrahydropyranyl group can be removed by treating underan acidic condition. As the acid, there may be used an inorganic acidsuch as hydrochloric acid, etc. The reaction can be carried out in asolvent such as an alcohol, etc., which does not interfere with thereaction. The reaction temperature normally is about 0° C. to about 100°C.

[Process B]

The compound (I) or (II) can be synthesized by subjecting the compound(IV) or (III), for example, to Suzuki reaction (cross condensationreaction by reacting an arylboric acid with an aryl halide or anaryloxytrifluoromethane sulfonate in the presence of palladiumcatalyst).

The reaction can be carried out by a method described in literature(Suzuki et al., Synth. Commum. 1981, Vol. 11, pp 513) or by a methodsimilar thereto.

The reaction temperature is about 20° C. to about 150° C., preferablyabout 60° C. to about 120° C. The reaction time is about 1 hour to about50 hours.

[Process C]

The compound (I) can be synthesized by reacting the compound (V) withthe compound (VI) and the compound (VII). The reaction can be carriedout by a manner described in literatures (Bhaduri et al., J.Heterocyclic Chem. 1987, Vol. 24, pp 23-25) or in a manner similar tothis method. The reaction temperature is about −70° C. to about 150° C.,preferably about 0° C. to about 100° C. The reaction time is about 5minutes to about 24 hours. The amount of the compound (VI) or (VII) usedis about 1.0 mol to about 10 mol, preferably about 1.0 mol to about 3.0mol per mol of the compound (V).

The reaction is usually carried out in an organic solvent which does notinterfere with the reaction. As the solvent which does not interferewith the reaction, the may be used an alcohol such as methanol, ethanol,etc.; an ether such as diethylether, dioxane, tetrahydrofuran (THF),etc.; a saturated hydrocarbon such as hexane, pentane, etc.; ahalogenated hydrocarbon such as dichloromethane, chloroform, etc.; anamide such as N,N-dimethylformamide, etc.; an aromatic hydrocarbon suchas benzene, toluene, etc. Single solvent or a mixed solvent consistingof two or more of these solvents in a conventional ratio, may be used.The reaction may be carried out by the addition of an acid or a base,etc. When the compound (V), (VI) or (VII) is protected by a protectivegroup, the protective group can be removed by a per se known method orby a method similar thereto to produce the compound (I).

A prodrug of the compound (I) means a compound which is converted to thecompound (I) with a reaction due to an enzyme, a gastric acid, etc.,under the physiological condition in vivo, that is, a compound which isconverted to the compound (I) with oxidation, reduction, hydrolysis,etc. due to an enzyme; a compound which is converted to the compound (I)with hydrolysis due to gastric acid, etc. A prodrug for compound (I) mayfor example be a compound obtained by subjecting an amino group in thecompound (I) to an acylation, alkylation or phosphorylation (e.g., acompound obtained by subjecting an amino group in compound (I) to aneicosanoylation, alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting a hydroxy in compound(I) to an acetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (I) to an ethylesterificatibn, phenylesterification,carboxymethylesterification, dimethylaminomethylesterification,pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification,phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification, methylamidation, etc.) and thelike. Any of these compounds can be produced from compound (I) by a perse known method.

A prodrug for compound (I) may be a compound which is converted intocompound (I) under a physiological condition as described in“Pharmaceutical Research and Development”, Vol. 7 (Design of molecules),pages 163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo,Japan).

The androgen receptor antagonistic drug of the present invention,including the compound (I) or the salt thereof, (hereinafter, sometimessimply referred to as the androgen receptor antagonistic drug of thepresent invention) has a superior androgen receptor antagonistic action,etc., a low toxicity and a less side-effect, and therefore is useful asa safe pharmaceuticals and as an androgen receptor antagonists, etc.

The pharmaceutical composition of the present invention, which containsthe androgen receptor antagonistic drug, shows superior androgenreceptor antagonism and (or) prostate-specific antigen (PSA)-producinginhibitory effect to a mammal (for example, mice, rats, hamsters,rabbits, cats, dogs, bovines, sheep, monkeys, humans, etc.), superiororal absorptivity and superior metabolic stability, and can be used asprophylactic or therapeutic agent for androgen receptor-relatingdisease, for example, hormone sensitivity disease in androgen-dependentstage and (or) androgen-independent stage, especially hormonesensitivity cancer in androgen-dependent stage and (or)androgen-independent stage (e.g., prostate cancer, uterine cancer,breast cancer, hypophyseal tumor, hepaticcancer, etc.) sex hormonesensitive diseases such as prostatic hypertrophy, endometriosis, uterinemyoma, precocious puberty, menstrual pain, amenorrhea, premenstrualsyndrome, multilocular ovary syndrome, etc. and agent for sterilization(or prophylaxis or treatment of sterility disease when rebound effectafter drug withdrawal is applied), etc.

Especially, the compound (I) or salt thereof of the present inventionshows antagonism to normal androgen receptor and (or) mutant receptor,and shows a superior prophylaxis or therapeutic effect for hormonesensitivity cancer in androgen-dependent stage and (or)androgen-independent stage.

Among the androgen receptor antagonistic drugs, an agent which showsantagonistic effect against a mutant androgen receptor or againstandrogen receptor having an increased sensitivity, is also useful asprophylactic or therapeutic agent for hormone sensitivity cancer inandrogen-dependent stage and (or) androgen-independent stage.

The pharmaceutical composition containing the androgen receptorantagonistic drug can be safely administered orally or non-orally (e.g.,topical, rectal, intravenous administration etc.) as a pharmaceuticalcomposition in a mixture with a commonly known pharmaceuticallyacceptable carrier, etc., such as tablets (including sugar-coatedtablets, film-coated tablets), powders, granules, capsules, (includingsoft capsules), liquid medicine, injections, suppositories, sustainedrelease preparations, etc. Injectable preparations can be administeredby an intravenous, intramuscular, subcutaneous or intra-tissue route ordirectly to the focuses.

As the pharmaceutically acceptable carrier which can be used for theproduction of the pharmaceutical composition of the present invention,there may be mentioned various organic or inorganic carriers which arecommonly used as preparation material. For example, excipients,lubricants, binders and disintegrators for producing solid preparations,solvent, solubilizer, suspending agents, isotonizing agent, buffer agentand soothing agent for producing a liquid preparation, etc. may bementioned. Further, a proper amount of additives such as preservatives,antioxidant, colorants, sweetening agents, adsorbing agent, wettingagents, etc. may be used, according to necessity.

As the excipients, there may be mentioned, for example, lactose,saccharose, D-mannitol, starch, corn starch, crystals cellulose, lightanhydrous silicic acid, etc.

As the lubricants, there may be mentioned, for example, magnesiumstearate, calcium stearate, talc, colloidal silica, etc.

As the binders, there may be mentioned, for example, crystals cellulose,saccharose, D-mannitol, dextrin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, starch, sucrose,gelatin, methyl cellulose, sodium carboxymethyl cellulose, etc.

As the disintegrators, there may be mentioned, for example, starch,carboxymethyl cellulose, carboxymethyl cellulose calcium, sodiumcarboxymethyl starch, L-hydroxypropyl cellulose, etc.

As the solvent, there maybe mentioned, for example, water for injection,alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil,etc.

As the solubilizer, there may be mentioned, for example, polyethyleneglycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, etc.

As the suspending agents, there may be mentioned, for example, asurfactants such as stearyltriethanolamine, sodium laurylsulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerin monostearate, etc.; hydrophilic polymer such aspolyvinyl alcohol, polyvinyl pyrolidone, sodium carboxymethyl cellulose,methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, etc.

As the isotonizing agent, there may be mentioned, for example, glucose,D-sorbitol, chloride sodium, glycerin, D-mannitol, etc.

As the buffer agent, there may be mentioned, for example, buffersolution such as a phosphate, an acetate, a carbonate, a citrate, , etc.

As the soothing agent, there may be mentioned, for example, benzylalcohol, etc.

As the preservatives, there may be mentioned, for example,paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol,dehydroacetic acid, sorbic acid, etc.

As the antioxidant, there may be mentioned, for example, a sulfite,ascorbic acid, α-tocopherol, etc.

The content of the androgen receptor antagonistic drug of the presentinvention in the pharmaceutical composition of the present invention canbe appropriately selected depending on the administration subject,administration route, diseases and the like. For example, the content ofthe androgen receptor antagonistic drug is usually from about 0.01% byweight to about 100% by weight, preferably from about 0.1% by weight toabout 50% by weight, more preferably from about 0.5% by weight to about20% by weight, based on the preparation while it differs depending onthe form of preparation.

The content of additives such as a carrier and the like in thepharmaceutical composition of the present invention differs depending onthe form of preparation, and is usually from about 1% by weight to about99.99% by weight, preferably from about 10% by weight to about 90% byweight, based on the preparation.

As a drug usable in combination the androgen receptor antagonistic drugof the present invention (hereinafter referred to as the other combineddrug for combination therapy), for example, a LH—RH derivative, etc. maybe mentioned.

As the LH—RH derivative, there may be mentioned, an LH—RH derivative orsalt thereof which is effective against hormone-dependent diseases,especially sex hormone-dependent diseases such as sex hormone-dependentcancers (e.g., prostate cancer, uterine cancer, breast cancer,hypophyseal tumor, hepatic cancer, etc.), prostatic hypertrophy,endometriosis, uterine myoma, precocious puberty, menstrual pain,amenorrhea, premenstrual syndrome, multilocular ovary syndrome, etc.,and sterilization (or prophylaxis or treatment of sterility diseaseswhen rebound effect after drug withdrawal is applied). Further, theremay be mentioned an LH—RH derivative or salt thereof which is effectiveagainst benign tumor or malignant tumor which is sex hormone-independentand LH—RH sensitivity.

Specific examples of the LH—RH derivatives or salt thereof includepeptides described in “Treatment-with GnRH analogs: Controversies andperspectives” issued in 1996 by The Parthenon Publishing Group Ltd., WO91-503165, JP 91-101695, JP 95-97334 and JP 94-259460, etc.

As the LH—RH derivative, there may be mentioned LH—RH agonists and LH—RHantagonists. As the LH—RH antagonist, there may be used, for example, aphysiologically active peptide represented by the formula:X-D2Nal-D4ClPhe-D3Pal-Ser-A-B-Leu-C-Pro-DAlaNH₂[wherein X is N(4H₂-furoyl)Gly or NAc; A is a residue selected fromNMeTyr, Tyr, Aph(Atz) and NMeAph(Atz); B is a residue selected fromDLys(Nic), DCit, DLys(AzaglyNic), DLys(AzaglyFur), DhArg(Et₂), DAph(Atz)and DhCi; and C is Lys(Nisp), Arg or hArg(Et₂)] or a salt thereof, etc.

As LH—RH agonist, there may be mentioned, for example, a physiologicallyactive peptide represented by the formula:5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z[wherein Y is a residue selected from DLeu, DAla, DTrp, DSer(tBu), D2Naland DHis(ImBzl); and Z is NH—C₂H₅ or Gly-NH₂] or salt thereof, etc.Especially, a peptide wherein Y is DLeu and Z is NH—C₂H₅ (that is,peptide A represented by the formula:5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C₂H_(5;)leuprorelin) or a salt thereof (e.g., acetate) is preferable.

The drug in which an androgen receptor antagonistic drug of the presentinvention and other combined drug are combined, (hereinafter referred toas the combination agent of the present invention) has low toxicity, andfor example, the androgen receptor antagonistic drug of the presentinvention or (and) the above-mentioned concomitant drug can be mixed,according to a known method per se, with a pharmacologically acceptablecarrier to give pharmaceutical compositions, for example, tablets(including a sugar-coated tablet, film-coated tablet), powders,granules, capsules (including a soft capsule), solutions, injections,suppositories, sustained release agents and the like which can be safelyadministered orally or parenterally (e.g., local, rectum, vein, and thelike). An injection can be administered by intravenous, intramuscular,subcutaneous or intra-tissue or directly to the lesion.

As the pharmaceutically acceptable carrier which may be used inproduction of the combination agent of the present invention, there maybe mentioned various organic or inorganic carriers which are commonlyused as preparation material. For example, excipients, lubricants,binders and disintegrators for producing a solid preparation, solvent,solubilizer, suspending agents, isotonizing agent, buffer agent andsoothing agent for producing a liquid preparation, etc. may bementioned. Further, a proper amount of additives such as preservatives,antioxidant, colorant, sweetening agents, adsorbing agent, wettingagents, etc. may be used, if necessary.

As the excipients, there may be mentioned, for example, lactose,saccharose, D-mannitol, starch, corn starch, crystalline cellulose,light anhydrous silicic acid, etc.

As the lubricants, there may be mentioned, for example, magnesiumstearate, calcium stearate, talc, colloidal silica, etc.

As the binders there may be mentioned, for example, crystals cellulose,saccharose, D-mannnitol, dextrin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyvinyl pyrolidone, starch, sucrose,gelatin, methyl cellulose, sodium carboxymethyl cellulose, etc.

As the disintegrators, there may be mentioned, for example, starch,carboxymethyl cellulose, carboxymethyl cellulose calcium, sodiumcarboxymethyl starch, L-hydroxypropyl cellulose, etc.

As the solvent, there may be mentioned, for example, water forinjection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil,olive oil, etc.

As the solubilizer, there may be mentioned, for example, polyethyleneglycol, propyleneglycol, D-mannnitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, etc.

As the suspending agents, there may be mentioned, for example, asurfactants such as stearyltriethanolamine, sodium laurylsulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerin monostearate, etc.; hydrophilic polymer such aspolyvinyl alcohol, polyvinyl pyrolidone, sodium carboxymethyl cellulose,methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, etc.

As the isotonizing agent, there may be mentioned, for example, glucose,D-sorbitol, chloride sodium, glycerin, D-mannitol, etc.

As the buffer agent, there may be mentioned, for example, a buffersolution such as a phosphate, an acetate, a carbonate, a citrate, etc.,etc.

As the soothing agent, there may be mentioned, for example, benzylalcohol, etc.

As the preservatives, there may be mentioned, for example,paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid, sorbic acid, etc.

As the antioxidant, there may be mentioned, for example, a sulfite salt,ascorbic acid, α-tocopherol, etc.

The compounding ratio of the androgen receptor antagonistic drug of thepresent invention to the other combined drug in the combination agent ofthe present invention can be appropriately selected depending on theadministration subject, administration route, diseases and the like.

For example, the content of the androgen receptor antagonistic drug ofthe present invention in the combination agent of the present inventiondiffers depending on the form of preparation, and is usually from about0.01% by weight to about 100% by weight,-preferably from about 0.1% byweight to about 50% by weight, more preferably from about 0.5% by weightto about 20% by weight, based on the preparation.

The content of the other combined drug in the combination agent of thepresent invention differs depending on the form of preparation, and isusually from about 0.01% by weight to about 100% by weight, preferablyfrom about 0.1% by weight to about 50% by weight, more preferably fromabout 0.5% by weight to about 20% by weight, based on the preparation.

The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof preparation, and is usually from about 1% by weight to about 99.99%by weight, preferably from about 10% by weight to about 90% by weight,based on the preparation.

When the androgen receptor antagonistic drug of the present inventionand the other combined drug for combination therapy are formulatedseparately, the same contents may be adopted.

These preparations can be produced by a per se known method commonlyused in the pharmaceutical manufacturing process.

For example, the androgen receptor antagonistic drug of the presentinvention and the other combined drug for combination therapy can bemade into an aqueous injection together with a dispersing agent (e.g.,Tween 80 (manufactured by Atlas Powder, US), HCO 60 (manufactured byNikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodiumalginate, hydroxypropylmethyl cellulose, dextrin and the like), astabilizer (e.g., ascorbic acid, sodium pyrosulfite, and the like), asurfactant (e.g., Polysorbate 80, macrogol and the like), a solubilizer(e.g., glycerin, ethanol and the like), a buffer (e.g., phosphoric acidand alkali metal salt thereof, citric acid and alkali metal saltthereof, and the like), an isotonizing agent (e.g., sodium chloride,potassium chloride, mannitol, sorbitol, glucose and the like), a pHregulator (e.g., hydrochloric acid, sodium hydroxide and the like), apreservative (e.g., ethyl p-oxybenzoate, benzoic acid, methylparaben,propylparaben, benzyl alcohol and the like), a dissolving agent (e.g.,conc. glycerin, meglumine and the like), a dissolution aid (e.g.,propylene glycol, sucrose and the like), a soothing agent (e.g.,glucose, benzyl alcohol and the like), and the like, or can bedissolved, suspended or emulsified in a vegetable oil such as olive oil,sesame oil, cotton seed oil, corn oil and the like or a dissolution aidsuch as propylene glycol and molded into an oily injection.

In the case of a preparation for oral administration, an excipient(e.g., lactose, sucrose, starch and the like), a disintegrating agent(e.g., starch, calcium carbonate and the like), a binder (e.g., starch,gum Arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropylcellulose and the like), a lubricant (e.g., talc, magnesium stearate,polyethylene glycol 6000 and the like) and the like, can be added to theandrogen receptor antagonistic drug of the present invention or theother combined drug, according to a known method per se, and the mixturecan be compression-molded, then if desirable, the molder product can becoated by a known method per se for the purpose of masking of taste,enteric property or durability, to obtain a preparation for oraladministration. As this coating agent, for example, hydroxypropylmethylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, celluloseacetate phthalate, hydroxypropylmethyl cellulose phthalate,hydroxymethyl cellulose acetate succinate, Eudragit (methacrylicacid/acrylic acid copolymer, manufactured by Rohm, DE), pigment (e.g.,iron oxide red, titanium dioxide, etc.) and the like, may be used. Thepreparation for oral administration may be either a quick releasepreparation or a sustained release preparation.

For example, in the case of a suppository, the androgen receptorantagonistic drug of the present invention and the other combined drugcan be made into an oily or aqueous solid, semisolid or liquidsuppository according to a known method per se. As the oily substrateused in the above-mentioned composition, for example, glycerides ofhigher fatty acids [e.g., cacao butter, Witebsols (manufactured byDynamite Novel, DE), etc.], intermediate grade fatty acids [e.g.,Myglyols (manufactured by Dynamite Novel, DE), etc.], or vegetable oils(e.g., sesame oil, soy bean oil, cotton seed oil and the like), and thelike are listed. Further, as the aqueous substrate, for example,polyethylene glycols, propylene glycol are listed, and as the aqueousgel substrate, for example, natural gums, cellulose derivatives, vinylpolymers, acrylic acid polymers and the like are listed.

As the above-mentioned sustained release agent, sustained releasemicrocapsules and the like are listed. For obtaining a sustained releasemicrocapsule, a known method per se can be adopted. It is preferable tomold into a sustained release preparation shown in [2] below.

A compound of the present invention is preferably molded into an oraladministration preparation such as a solid preparation (e.g., powder,granule, tablet, capsule, etc.) and the like, or molded into a rectumadministration preparation such as a suppository. Particularly, an oraladministration preparation is preferable.

The other combined drug can be made into the above-mentioned drug formdepending on the kind of drug.

[1] An injection of the androgen receptor antagonistic drug or the othercombined drug and preparation method thereof, [2] a quick releasepreparation of sustained release preparation and the androgen receptorantagonistic drug or the other combined drug and preparation thereof and[3] a sublingual tablet, a buccal or an intraoral quick integratingagent of the androgen receptor antagonistic drug or the other combineddrug or preparation thereof are specifically mentioned below.

[1] Injectable Preparation and its Production

An injectable preparation prepared by dissolving the androgen receptorantagonistic drug of the present invention or the other combined drugfor combination therapy in water is preferable. This injectablepreparation may be allowed to contain a benzoate and/or a salicylate.

The injection is obtained by dissolving the androgen receptorantagonistic drug or the other combined drug of the present invention,and if desirable, a benzoate and/or a salicylate, into water.

As the above-mentioned salts of benzoic acid and salicylic acid, forexample, salts of alkali metals such as sodium, potassium and the like,salts of alkaline earth metals such as calcium, magnesium and the like,ammonium salts, meglumine salts, organic acid salts such as tromethamoland the like, etc. are listed.

The concentration of the androgen receptor antagonistic drug or theother combined drug of the present invention in an injection is from 0.5w/v % to 50 w/v %, preferably from about 3 w/v % to about 20 w/v %. Theconcentration of a salt of benzoic acid or/and a salt of salicylic acidis from 0.5 w/v % to 50 w/v %, preferably from 3 w/v % to 20 w/v %.

Conventional additives for use in an injection may be appropriatelyadded in a preparation of the present invention. Examples of theadditives include a stabilizer (e.g. ascorbic acid, sodium pyrosulfite,and the like), a surfactant (e.g., Polysorbate 80, macrogol and thelike), a solubilizer (e.g., glycerin, ethanol and the like), a buffer(e.g., phosphoric acid and alkali metal salt thereof, citric acid andalkali metal salt thereof, and the like), an isotonizing agent (e.g.,sodium chloride, potassium chloride, and the like), a dispersing agent(e.g., hydroxypropylmethyl cellulose, dextrin), a pH regulator (e.g.,hydrochloric acid, sodium hydroxide and the like), a preservative (e.g.,ethyl p-oxybenzoate, benzoic acid and the like), a dissolving agent(e.g., conc. glycerin, meglumine and the like), a dissolution aid (e.g.,propylene glycol, sucrose and the like), a soothing agent (e.g.,glucose, benzyl alcohol and the like), and the like. These additives aregenerally blended in a usual proportion employed in an injection.

It is advantageous that the pH of the injection is controlled from 2 to12, preferably from 2.5 to 8.0 by addition of a pH regulator.

An injectable preparation is obtained by dissolving the compound of thepresent invention or the other combined drug for combination therapy andif desirable, a salt of benzoic acid and/or a salt of salicylic acid,and if necessary, the above-mentioned additives into water. These may bedissolved in any order, and can be appropriately dissolved in the samemanner as in a conventional method of producing an injection.

An aqueous solution for injection may be advantageously heated,alternatively, for example, filter sterilization, high pressure heatsterilization and the like can be conducted in the same manner as for ausual injection, to provide an injection.

It may be advantageous that an aqueous solution for injection issubjected to high pressure heat sterilization at 100° C. to 121° C. for5 minutes to 30 minutes.

Further, a preparation endowed with the antibacterial property of asolution may also be produced so that it can be used as a preparationwhich is divided and administered multiple-times.

[2] A Sustained Release Preparation or a Rapid Release Preparation, andits Production

Preffered is a sustained release preparation which is obtained, bycoating a core containing the androgen receptor antagonistic drug or theother combined drug of the present invention with a film agent such as awater-insoluble substance, swellable polymer and the like, if desirable.For example, a sustained release preparation for oral administration ofonce administration per day type is preferable.

As the water insoluble substance used in film forming agent, there maybe mentioned, for example, a cellulose ether such as ethyl cellulose,butyl cellulose, etc.; a cellulose ester such as cellulose acetate,cellulose propionate, etc.; a polyvinyl ester such as polyvinyl acetate,polyvinyl butyrate, etc.; an acrylic acid polymer such as acrylicacid/methacrylic acid copolymer, methylmethacrylate copolymer,ethoxyethyl methacrylate/cinnamoethylmethacrylate/aminoalkylmethacrylate copolymer, polyacrylic acid, polymethacrylic acid,methacrylic acid alkyl amide copolymer, poly(methacrylic acid methyl),polymethacrylate, polymethacryl amide, amino alkyl methacrylatecopolymer, poly(methacrylic acid anhydride), glycidyl methacrylatecopolymer, specially an Eudragit (manufactured by Rohm Pharma) such asEudragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (copolymer ofacrylic acid ethyl/methyl methacrylate/chlorotrimethylmethacrylate/ethylammonium), Eudragit NE-30D (copolymer of methyl methacrylate/ethylacrylate), etc., a hydrogenated oil such as hardened caster oil (e.g.,Lovely wax (Freunt), etc.), etc.; a wax such as carnauba wax, fatty acidglycerin ester, paraffin, etc.; polyglycerin fatty acid ester, etc.

As the swellable polymer, a polymer having acidic dissociating group andpH-dependent swelling property, is preferable, and a polymer havingacidic dissociating group which swells little in a area such as stomachand swells in a neutral area such as the small intestine or the largeintestine.

As the polymer having acidic dissociating group and pH-dependentswelling property, there may be mentioned, crosslinkable polyacrylicpolymer such as Carbomer 934P, 940, 941, 974P, 980, 1342 and the like,polycarbophil, carcium polycarbophil (the last two are manufactured byBF Goodrich), Hibiswako 103, 104, 105, 304 (all are manufactured by WakoPure Chemical Co., Ltd.), and the like, are listed. The film formingagent used in a sustained release preparation may further contain ahydrophilic substance.

As the hydrophilic substance, there maybe mentioned, for example, apolysaccharide such as pullulan, dextrin, arginic acid alkalimetal salt,etc.; a polysaccharide having a hydroxyalkyl group or a carboxyalkylgroup such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose,sodium carboxymethyl cellulose, etc.; methyl cellulose; polyvinylpyrolidone; polyvinyl alcohol; polyethylene glycol; etc.

The content of water insoluble substance in the film forming agent ofsustained release preparation is about 30% (w/w) to about 90% (w/w),preferably about 35% (w/w) to about 80% (w/w), and more preferably about40% (w/w) to about 75% (w/w). The content of swellable polymer is about3% (w/w) to about 30% (w/w), preferably about 3% (w/w) to about 15%(w/w) The film forming agent may further contain a hydrophilicsubstance, in this case, the content of the hydrophilic substance in thefilm forming agent is about 50% (w/w) or less, preferably about 5% (w/w)to about 40% (w/w), and more preferably about 5% (w/w) to about 35%(w/w). This % (w/w) indicates % by weight based on a film agentcomposition which is obtained by removing a solvent (e.g., water, loweralcohols such as methanol, ethanol and the like) from a film agentsolution.

The sustained release preparation is produced by preparing a corecontaining a drugs as exemplified below, then, coating the resulted corewith a film agent liquid prepared by heating to melt a water-insolublesubstance, swellable polymer and the like or by dissolving or dispersingit in a solvent. I. Preparing of Cores Containing an Active Ingredient

The form of core containing a drug to be coated with a film agent(hereinafter, sometimes simply referred to as core) is not particularlyrestricted, and preferably, the core is formed into particles such as agranule or fine particle.

When the core is composed of granules or fine particles, the averageparticle size thereof is preferably from about 150 to about 2,000 μm,further preferably, from about 500 μm to 1,400 μm.

Preparation of the core can be effected by a usual production method.For example, a suitable excipient, binding agent, disintegrating agent,lubricant, stabilizer and the like are mixed into a drug, and themixture is subjected to a wet extrusion granulating method, fluidizedbed granulating method or the like, to prepare a core.

The content of drugs in a core is from about 0.5% (w/w) to about 95%(w/w), preferably from about 5.0% (w/w) to about 80% (w/w), furtherpreferably from about 30% (w/w) to about 70% (w/w).

As the excipient contained in the core, for example, saccharides such assucrose, lactose, mannitol, glucose and the like, starch, crystallinecellulose, calcium phosphate, corn starch and the like are used. Amongthem, crystalline cellulose, corn starch are preferable.

As the binders, there may be used, for example, polyvinyl alcohol,hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrolidone,Pulronick F68, arabic gum, gelatin, starch, etc. As the disintegrators,there may be used, for example, carboxymethyl cellulose calcium(ECG505), croscarmellose sodium (Ac-Di-Sol), crosslinkable polyvinylpyrolidone (crospovidone), low substituted hydroxypropyl cellulose(L-HPC), etc. Among these, hydroxypropyl cellulose, polyvinylpyrolidone, low substituted hydroxypropyl cellulose are preferable. Asthe lubricants or the aggregation inhibitor, there may be used, forexample, talc, magnesium stearate and an inorganic salt thereof. As thelubricant, there may be used a polyethylene glycol, etc. As thestabilizing agent, there may be used an acid such as tartaric acid,citric acid, succinic acid, fumaric acid, maleic acid, etc.

A core can also be prepared by, in addition to the above-mentioned, forexample, a rolling granulation method in which a drug or a mixture of adrug with an excipient, lubricant and the like is added portionwise ontoan inert carrier particle which is the core of the core while spraying abinder dissolved in a suitable solvent such as water, lower alcohol(e.g., methanol, ethanol and the like) and the like, a pan coatingmethod, a fluidized bed coating method or a melt granulating method. Asthe inert. carrier particle, for example, those made of sucrose,lactose, starch, crystalline cellulose, waxes can be used, and theaverage particle size thereof is preferably from about 100 μm to about1,500 μm.

For the purpose of separating the drug contained in the core from thefilm agent, the surface of the core may be coated with a protectiveagent. As the protective agent, for example, the above-mentionedhydrophilic substances, water-insoluble substances and the like areused. As the protective agent, preferably polyethylene glycol, andpolysaccharides having a hydroxyalkyl group or carboxyalkyl group areused, more preferably, hydroxypropylmethyl cellulose and hydroxypropylcellulose are used. The protective agent may contain, as stabilizer,acids such as tartaric acid, citric acid, succinic acid, fumaric acid,maleic acid and the like, and lubricants such as talc and the like. Whenthe protective agent is used, the coating amount is from about 1% (w/w)to about 15% (w/w), preferably from about 1% (w/w) to about 10% (w/w),further preferably from about 2% (w/w) to about 8% (w/w), based on thecore.

The coating of the protective agent can be carried out by a usualcoating method, and specifically, the coating can be carried out byspraying the protective agent by a fluidized bed coating method, pancoating method and the like.

II. Coating of Core with Film Agent

A core obtained in the above-mentioned step I is coated with a filmagent solution obtained by heat-solving the above-mentionedwater-insoluble substance and pH-dependent swellable polymer, and ahydrophilic substance, or by dissolving or dispersing them in a solvent,to give a sustained release preparation.

As the method for coating a core with a film agent solution, forexample, a spray coating method and the like are listed.

The composition ratio of a water-insoluble substance, swellable polymerand hydrophilic substance in a film agent solution is appropriatelyselected so that the contents of these components in a coated film arethe above-mentioned contents, respectively.

The coating amount of a film agent is from about 1% (w/w) to about 90%(w/w), preferably from about 5% (w/w) to about 50% (w/w), furtherpreferably from about 5% (w/w) to about 35% (w/w), based on a core (notincluding coating amount of protective agent).

As the solvent in a film agent solution, water or an organic solvent canbe used alone or in admixture thereof. In the case of use in admixture,the mixing ratio of water to an organic solvent (water/organic solvent:by weight) can be varied in the range from 1 to 100%, and preferablyfrom about 1% to about 30%. The organic solvent is not particularlyrestricted providing it dissolves a water-insoluble substance, and forexample, lower alcohols such as methyl alcohol, ethyl alcohol, isopropylalcohol, n-butyl alcohol and the like, lower alkanones such as acetoneand the like, acetonitrile, chloroform, methylene chloride and the likeare used. Among them, lower alcohols are preferable, and ethyl alcoholand isopropyl alcohol are particularly preferable. Water, and a mixtureof water with an organic solvent are preferably used as a solvent for afilm agent. In this case, if necessary, an acid such as tartaric acid,citric acid, succinic acid, fumaric acid, maleic acid and the like mayalso be added into a film agent solution for stabilizing the film agentsolution.

An operation of coating by spray coating can be effected by a usualcoating method, and specifically, it can be effected by spray-coating afilm agent solution onto a core, for example, by a fluidized bed coatingmethod, pan coating method and the like. In this case, if necessary,talc, titanium oxide, magnesium stearate, calcium stearate, lightanhydrous silicic acid and the like may also be added as a lubricant,and glycerin fatty ester, hardened castor oil, triethyl citrate, cetylalcohol, stearyl alcohol and the like may also be added as aplasticizer.

After coating with a film agent, if necessary, an antistatic agent suchas talc and the like may be mixed.

The quick release preparation may be liquid (solution, suspension,emulsion and the like) or solid (particle, pill, tablet and the like).Oral agents and parenteral agents such as an injection and the like areused, and oral agents are preferable.

The quick release preparation, usually, may contain, in addition to anactive component drug, also carriers, additives and excipientsconventionally used in the production field (hereinafter, sometimesabbreviated as excipient). The preparation excipient used is notparticularly restricted providing it is an excipient ordinarily used asa preparation excipient. For example, as the excipient for an oral solidpreparation, lactose, starch, corn starch, crystalline cellulose (AvicelPH101, manufactured by Asahi Chemical Industry Co., Ltd., and the like),powder sugar, granulated sugar, mannitol, light anhydrous silicic acid,magnesium carbonate, calcium carbonate, L-cysteine and the like arelisted, and preferably, corn starch and mannitol and the like arelisted. These excipients can be used alone or in combination of two ormore. The content of the excipient is, for example, from about 4.5 w/w %to about 99.4 w/w %, preferably from about 20 w/w % to about 98.5 w/w %,further preferably from about 30 w/w % to about 97 w/w %, based on thetotal amount of the quick release preparation.

The content of a drug in the quick release preparation can beappropriately selected in the range from about 0.5% to about 95%,preferably from about 1% to about 60% based on the total amount of thequick release preparation.

When the quick release preparation is an oral solid preparation, itusually contains, in addition to the above-mentioned components, also anintegrating agent. As this integrating agent, there are used, forexample, carboxymethyl cellulose calcium (ECG-505, manufactured byGotoku Yakuhin), croscarmelose sodium (for example, Actisol,manufactured by Asahi Chemical Industry Co., Ltd.), crospovidone (forexample, Colicone CL,: manufactured by BASF), low-substitutedhydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.),carboxymethyl starch (manufactured by Matsutani Kagaku K. K.),carboxymethylstarch sodium (Exprotab, manufactured by Kimura Sangyo),partially α-nized starch (PCS, manufactured by Asahi Chemical IndustryCo., Ltd.), and the like are used, and for example, those whichdisintegrate a granule by adsorbing water in contact with water, causingswelling, or making a channel between an effective ingredientconstituting the core and an excipient, can be used. Thesedisintegrating agents can be used alone or in combination of two ormore. The amount of the disintegrating agent used is appropriatelyselected depending on the kind and blending amount of a drug used,design of releasing property, and the like, and for example, from about0.05 w/w % to about 30 w/w %, preferably from about 0.5 w/w % to about15 w/w %, based on the total amount of the quick releasing agent.

When the quick release preparation is an oral solid preparation, it mayfurther contain, in addition to the above-mentioned composition, ifdesired, additives conventional in solid preparations. As such anadditive, there are used, for example, a binder (e.g., sucrose, gelatin,gum Arabic powder, methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxylmethyl cellulose,polybinylpyrrolidone, pluran, dextrin and the like), a lubricant (e.g.,polyethylene glycol, magnesium stearate, talc, light anhydrous silicicacid (for example, aerosil (Nippon Aerosil)), a surfactant (e.g.,anionic surfactants such as sodium alkylsulfate and the like, nonionicsurfactants such as polyoxyethylene fatty acid ester and polyoxyethylenesorbitan fatty acid ester, polyoxyethylene castor oil derivatives andthe like), a coloring agent (e.g., tar coloring matter, caramel, ironoxide red, titanium oxide, riboflavins), if necessary, an appetizingagent (e.g., sweetening agent, aroma chemical and the like), anadsorbent, preservative, wetting agent, antistatic agent, and the like.Further, as the stabilizer, an organic acid such as tartaric acid,citric acid, succinic acid, fumaric acid and the like may also be added.

As the above-mentioned binder, hydroxypropyl cellulose, polyethyleneglycol and polyvinylpyrrolidone and the like are preferably used.

The quick releasing reparation can be prepared by, based on a usualtechnology of producing preparations, mixing the above-mentionedcomponents, and if necessary, further kneading the mixture, and moldingit. The above-mentioned mixing is conducted by generally used methods,for example, mixing, kneading and the like. Specifically, when a quickrelease preparation is formed, for example, into a particle, it can beprepared, according to the same means as in the above-mentioned methodfor preparing a core of a sustained release preparation, by mixing thecomponents using a vertical granulator, universal kneader (manufacturedby Hata Tekkosho), fluidized bed granulator FD-5S (manufactured byPulek), and the like, then, subjecting the mixture to a wet extrusiongranulation method, fluidized bed granulation method and the like.

Thus obtained quick releasing preparation and sustained releasingpreparation may be themselves made into products or made into productsappropriately together with preparation excipients and the like,separately, by an ordinary method, then, may be administeredsimultaneously or may be administered in combination at anyadministration interval, or they may be themselves made into one oralpreparation (e.g., granule, fine particle, tablet, capsule and the like)or made into one oral preparation together with preparation excipientsand the like. It may also be permissible that they are made intogranules or fine particles and filled in the same capsule to be used asa preparation for oral administration.

[3] Sublinguial, Buccal or Intraoral Quick Disintegrating Agent andPreparation Thereof

Sublinguial, buccal or intraoral quick disintegrating agents may be asolid preparation such as tablet and the like, or may be an oral mucosamembrane patch (film).

As the sublinguial, buccal or intraoral quick. disintegrating agent, apreparation containing the androgen receptor antagonistic drug of thepresent invention or the combination drug and an excipient ispreferable. It may contain also auxiliary agents such as a lubricant,isotonizing agent, hydrophilic carrier, water-dispersible polymer,stabilizer and the like. Further, for easy absorption and increase in invivo use efficiency, β-cyclodextrin or β-cyclodextrin derivatives (e.g.,hydroxypropyl-β-cyclodextrin and the like) and the like may also becontained.

As the above-mentioned excipient, lactose, sucrose, D-mannitol, starch,crystalline cellulose, light anhydrous silicic acid and the like arelisted. As the lubricant, magnesium stearate, calcium stearate, talc,colloidal silica and the like are listed, and particularly, magnesiumstearate and colloidal silica are preferable. As the isotonizing agent,sodium chloride, glucose, fructose, mannitol, sorbitol, lactose,saccharose, glycerin, urea and the like are listed, and particularly,mannitol is preferable. As the hydrophilic carrier, swellablehydrophilic carriers such as crystalline cellulose, ethyl cellulose,crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid,silicic acid, dicalcium phosphate, calcium carbonate and the like arelisted, and particularly, crystalline cellulose (e.g., fine crystallinecellulose and the like) is preferable. As the water-dispersible polymer,gums (e.g., gum tragacanth, acacia gum, cyamoposis gum), alginates(e.g., sodium alginate), cellulose derivatives (e.g., methyl cellulose,carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose), gelatin, water-solublestarch, polyacrylic acids (e.g., Carbomer), polymethacrylic acid,polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone,polycarbofil, ascorbate, palmitates and the like are listed, andhydroxypropylmethyl cellulose, polyacrylic acid, alginate, gelatin,carboxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycol andthe like are preferable. Particularly, hydroxypropylmethyl cellulose ispreferable. As the stabilizer, cysteine, thiosorbitol, tartaric acid,citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfiteand the like are listed, and particularly, citric acid and ascorbic acidare preferable.

The sublinguial, buccal or intraoral quick disintegrating agent can beproduced by mixing the androgen receptor antagonistic drug of thepresent invention or the other combined drug and an excipient by amethod known per se. Further, if desired, auxiliary agents such as alubricant, isotonizing agent, hydrophilic carrier, water-dispersiblepolymer, stabilizer, coloring agent, sweetening agent, preservative andthe like may be mixed. The sublingual, buccal or intraoral quickdisintegrating agent is obtained by mixing the above-mentionedcomponents simultaneously or at a time interval, then subjecting themixture to tablet-making molding under pressure. For obtaining suitablehardness, it may also be permissible that the materials are moistened byusing a solvent such as water, alcohol and the like if desired beforeand after the tablet making process, and after the molding, thematerials are dried, to obtain a product.

In the case of molding into a mucosa membrane patch (film), the androgenreceptor antagonistic drug of the present invention or the othercombined drug and the above-mentioned water-dispersible polymer(preferably, hydroxypropyl cellulose, hydroxypropylmethyl cellulose),excipient and the like are dissolved in a solvent such as water and thelike, and the resulted solution is cast to give a film. Further,additives such as a plasticizer, stabilizer, antioxidant, preservative,coloring agent, buffer, sweetening agent and the like may also be added.For imparting suitable elasticity to the film, glycols such aspolyethylene glycol, propylene glycol and the like may be contained, orfor enhancing adhesion of the film to an intraoral mucosamembranelining, a bio-adhesive polymer (e.g., polycarbofil, carbopol) may alsobe contained. In the casting, absolution is poured on the non-adhesivesurface, spread to uniform thickness (preferably, about 10 micron toabout 1,000 micron) by an application tool such as a doctor blade andthe like, then, the solution is dried to form a film. It may beadvantageous that thus formed film is dried at room temperature or underheat, and cut into given area.

As the preferable intraoral quick disintegrating agent, there are listedsolid quick scattering dose agents composed of a network body comprisingthe androgen receptor antagonistic drug of the present invention or thecombination drug, and a water-soluble or water-diffusible carrier whichis inert to the androgen receptor antagonistic drug of the presentinvention or the other combined drug, are listed. This network body isobtained by sublimating a solvent from the solid composition constitutedof a solution prepared by dissolving the androgen receptor antagonisticdrug of the present invention or the combination drug in a suitablesolvent.

It is preferable that the composition of an intraoral quickdisintegrating agent contains a matrix forming agent and a secondarycomponent, in addition to the androgen receptor antagonistic drug of thepresent invention or the other combined drug.

Examples of the matrix forming agent include animal proteins orvegetable proteins such as gelatins, dextrins, soybean, wheat andpsyllium seed protein and the like; rubber substances such as gumArabic, guar gum, agar, xathane gum and the like; polysaccharides;alginic acids; carboxymethyl celluloses; caragenans; dextrans; pectines;synthetic polymers such as polyvinylpyrrolidone and the like; substancesderived from a gelatin-gum Arabic complex, and the like. Further,saccharides such as mannitol, dextrose, lactose, galactose, trehaloseand the like; cyclic saccharides such as cyclodextrin and the like;inorganic salts such as sodium phosphate, sodium chloride and aluminumsilicate and the like; amino acids having 2 to 12 carbon atoms such asglycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline,L-isoleucine, L-leucine, L-phenylalanine-and the like, are contained.

One or more of the matrix forming agent(s) can be introduced in asolution or suspension before solidification. Such as matrix formingagent may be present in addition to a surfactant, or maybe present whilea surfactant being excluded. The matrix forming agents aid to maintainthe androgen receptor antagonistic drug of the present invention or theother combined drug in the solution or suspension in diffused condition,in addition to formation of the matrix.

The composition may contain secondary components such as a preservative,antioxidant, surfactant, thickening agent, coloring agent, pHcontrolling agent, flavoring agent, sweetening agent, food taste maskingagent and the like. As the suitable coloring agent, there are listedred, black and yellow iron oxides, and FD & C dyes such as FD & C Blue2, FD & C Red 40 and the like manufactured by Elis and Eberald. Examplesof the suitable flavoring agent include mint, raspberry, licorice,orange, lemon, grape fruit, caramel, vanilla, cherry, grape flavor andcombinations thereof. Examples of the suitable pH controlling agentinclude citric acid, tartaric acid, phosphoric acid, hydrochloric acidand maleic acid. Examples of the suitable sweetening agent includeaspartame, acesulfame K and thaumatin and the like. Examples of thesuitable food taste masking agent include sodium bicarbonate, ionexchange resin, cyclodextrin-containing compounds, adsorbent substancesand microcapsulated apomorphine.

The preparation contains the androgen receptor antagonistic drug of thepresent invention or the other combined drug in an amount usually fromabout 0.1% by weight to about 50% by weight, preferably from about 0.1%by weight to about 30% by weight, and preferable are preparations (suchas the above-mentioned sublingual agent, buccal and the like) which candissolve 90% or more the androgen receptor antagonistic drug of thepresent invention or the other combined drug (into water) within thetime range of about 1 minute to about 60 minutes, preferably of about 1minute to 15 minutes, more preferably of about 2 minutes to 5 minutes,and intraoral quick disintegrating preparations which are disintegratedwithin the range of 1 second to 60 seconds, preferably of 1 to 30seconds, further preferably of 1 to 10 seconds after place in an oralcavity.

The content of the above-mentioned excipient in the whole preparation isfrom about 10% by weight to about 99% by weight, preferably from about.30% by weight to about 90% by weight. The content of β-cyclodextrin orβ-cyclodextrin derivative in the whole preparation is from 0 to about30% by weight. The content of the lubricant in the whole preparation isfrom about 0.01% by weight to about 10% by weight, preferably from about1% by weight to about 5% by weight. The content of the isotonizing agentin the whole preparation is from about 0.1% by weight to about 90% byweight, preferably, from about 10% by weight to about 70% by weight. Thecontent of the hydrophilic carrier agent in the whole preparation isfrom about 0.1% by weight to about 50% by weight, preferably, from about10% by weight to about 30% by weight. The content of thewater-dispersible polymer in the whole preparation is from about 0.1 toabout 30% by weight, preferably, from about 10% by weight to about 25%by weight. The content of the stabilizer in the whole preparation isfrom about 0.1% by weight to about 10% by weight, preferably, from about1% by weight to about 5% by weight. The above-mentioned preparation mayfurther contain additives such as a coloring agent, sweetening agent,preservative and the like, if necessary.

The dosage of a combination agent of the present invention differsdepending on the kind of the compound (I) of the present invention, age,body weight, condition, drug form, administration method, administrationperiod and the like, and for example, for one breast cancer patient(adult, body weight: about 60 kg), the combination agent is administeredintravenously, at a dose of about 0.01 mg/kg/day to about 1,000mg/kg/day, preferably about 0.01 mg/kg/day to about 100 mg/kg/day, morepreferably about 0.1 mg/kg/day to about 100 mg/kg/day, particularlyabout 0.1 mg/kg/day to about 50 mg/kg/day, especially about 1.5mg/kg/day to about 30 mg/kg/day, in terms of the androgen receptorantagonistic drug of the present invention or the other combined drug,respectively, once or several time in division a day. Of course, sincethe dose as described above varies depending on various conditions,amounts smaller than the above-mentioned dosage may sometimes besufficient, further, amounts over that range sometimes have to beadministered.

The amount of the other combined drug can be set at any value unlessside effects are problematical. The daily dosage in terms of thecombination drug differs depending on the severity, age, sex, bodyweight, sensitivity difference of the subject, administration period,interval, and nature, pharmacy, kind of the pharmaceutical preparation,kind of effective ingredient, and the like, and not particularlyrestricted, and the amount of a drug is, in the case of oraladministration for example, usually from about 0.001 mg to about 2,000mg, preferably from about 0.01 mg to about 500 mg, further preferablyfrom about 0.1 mg to about 100 mg, per 1 kg of a mammal and this isusually administered once to 4-times in division a day.

In administration of the combination agent of the present invention, theandrogen receptor antagonistic drug of the present invention may beadministered after administration of the other combined drug or theother combined drug may be administered after administration of theandrogen receptor antagonistic drug of the present invention, thoughthey may be administered simultaneously. When administered at a timeinterval, the interval differs depending on the effective ingredient,drug form and administration method, and for example, when the othercombined drug is administered first, a method in which the androgenreceptor antagonistic drug of the present invention is administeredwithin time range of from 1 minute to 3 days, preferably from 10 minutesto 1 day, more preferably from 15 minutes to 1 hour after administrationof the combined drug is exemplified. When the androgen receptorantagonistic drug of the present invention is administered first, amethod in which the combined drug is administered within time range offrom 1 minute to 1 day, preferably from 10 minutes to 6 hours, morepreferably from 15 minutes to 1 hour after administration of theandrogen receptor antagonistic drug of the present invention isexemplified.

In a preferable administration method, for example, the other combineddrug which has been formed into an oral administration preparation isadministered orally at a daily dose of about 0.001 mg/kg to about 200mg/kg, and 15 minutes later, the androgen receptor antagonistic drug ofthe present invention which has been formed into an oral administrationpreparation is administered orally at a daily dose of about 0.005 mg/kgto about 100 mg/kg.

EXAMPLES

Further, the present invention is specifically explained by thefollowing Reference Examples and Examples, but these are merelypractical examples and not limiting the present invention, and theseExamples may be changed to such an extent that they do not deviate fromthe scope of the present invention.

In the following Reference Examples, “room temperature” means usuallyabout 10° C. to about 35° C., and “%” means weight percent unlessotherwise specified. However, “yield” is indicated by mol/mol %.

Further, the other abbreviations used in the description have themeanings shown below.

-   s: singlet-   brs: broad singlet-   d: doublet-   t: triplet-   q: quartet-   dd: double doublet-   ddd: double double doublet-   dt: double triplet-   m: multiplet-   br: broad-   J: coupling constant-   Hz: Hertz-   CDCl₃: Heavy chloroform-   ¹H-NMR: Proton nuclear magnetic resonance-   Me: methyl

Reference Example 1

Production of 1-nitro-4-[(1E)-2-nitro-1-propenyl]benzene

To a mixture of 4-nitrobenzaldehyde (23.9 g) and nitro ethane (30 g) wasadded n-butylamine (1.2 g) and the mixture was heated at 100° C. for 18hours. The reaction mixture was concentrated. To the residue was addedethanol and the resulting crystals were collected by filtration. Thecrystals were further washed with ethanol and diisopropyl ether toobtain the titled compound (15.6 g) as yellow crystals.

¹H-NMR (CDCl₃) δ 2.46 (3H, s), 7.60 (2H, d, J=8.7 Hz), 8.09 (1H, s),8.33 (2H, d, J=8.7 Hz).

IR (KBr): ν 3113, 3076, 3057, 2984, 2941, 2839, 1599, 1520 cm⁻¹.

Reference Example 2

Production of Methyl 4-bromo-2,5-dimethyl-1H-pyrrole-3-carboxylate

To a solution of methyl 2,5-dimethyl-1H-pyrrole-3-carboxylate (6.85 g)and triethylamine (8.7 ml) in dichloromethane (270 ml) was addedpyridine perbromohydrobromide (15.7 g) little by little at 0° C. Thereaction mixture was stirred at the same temperature for 2 hours andpoured into saturated sodium chloride solution. The reaction mixture wasextracted with ethyl acetate, and the ethyl acetate layer was dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) andrecrystallized from ethyl acetate-hexane to obtain the titled compound(7.59 g) as yellow crystals.

¹H-NMR (CDCl₃) δ 2.19 (3H, s), 2.47 (3H, s), 3.82 (3H, s), 8.20 (1H, s).

Reference Example 3

Production of Ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate

By using ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (5.15 g), thereaction and purification were carried out in the same manner asReference Example 2 to obtain the titled compound (4.43 g) as colorlesscrystals.

¹H-NMR (CDCl₃) δ1.37 (3H, t, J=6.8 Hz), 2.26 (3H, s), 2.28 (3H, s), 4.32(2H, q, J=6.8 Hz), 9.32 (1H, s).

Reference Example 4

Production of Methyl1-benzyl-4-bromo-2,5-dimethyl-1H-pyrrole-3-carboxylate

A suspension of sodium hydride (60% suspension of sodium hydride in oil,0.26 g) in tetrahydrofuran (30 ml) was cooled on a ice bath, and to thesuspension was added the compound (1.01 g) produced in Reference Example2. The reaction mixture was heated at the same temperature for 30minutes. To the reaction mixture was added benzyl bromide (0.57 ml), andthe reaction mixture was stirred at room temperature for 4 hours. Thereaction mixture was poured into saturated aqueous solution of sodiumchloride and the reaction mixture was extracted with ethyl acetate. Theethyl acetate layer was dried over magnesium sulfate and concentrated.The residue was purified by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate), and recrystallized from ethylacetate-hexane to obtain the titled compound (0.75 g) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 2.15 (3H, s), 2.45 (3H, s), 3.84 (3H, s), 5.08 (2H, s),6.8-7.0 (2H, m), 7.2-7.4 (3H, m).

Reference Example 5

Production of1-benzyl-4-(methoxycarbonyl)-2,5-dimethyl-1H-pyrrol-3-ylboronic Acid

To a solution of the compound (550 mg) produced in Reference Example 4in tetrahydrofuran (8.5 ml) was added dropwise a solution ofbutyllithium in hexane (1.6 mol/1, 1.1 ml) at −78° C. The reactionmixture was stirred at the same temperature for 1 hour, and then asolution of trimethyl borate (1.94 ml) in tetrahydrofuran (34 ml) wasadded, and the reaction mixture was further stirred for 1 hour. To thereaction mixture was added a mixture of water (5 ml) and methanol (5ml), and the temperature of the reaction mixture was then elevated up toroom temperature. The reaction mixture was poured into a saturatedaqueous solution of sodium chloride and extracted with ethyl acetate.The ethyl acetate layer was dried over magnesium sulfate andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to obtain the titled compound (413 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 2.41 (3H, s), 2.46 (3H, s), 3.86 (3H, s), 6.8-7.0 (2H,m), 7.2-7.4 (3H, m).

Reference Example 6

Production of Methyl4-bromo-1-(4-fluorobenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (3.71 g) produced in Reference Example 2 and4-fluorobenzyl bromide (2.0 ml), the reaction and purification werecarried out in the manner as Example 2 to obtain the titled compound(4.12 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.14 (3H, s), 2.44 (3H, s), 3.85 (3H, s), 5.05 (2H, s),6.8-7.0 (2H, m), 7.0-7.2 (2H, m).

Reference Example 7

Production of1-(4-fluorobenzyl)-4-(methoxycarbonyl)-2,5-dimethyl-1H-pyrrol-3-ylboronicAcid

By using the compound (1.04 g) produced in Reference Example 6, thereaction and purification were carried out in the same manner asReference Example 5 to obtain the titled compound (510 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 2.40 (3H, s), 2.46 (3H, s), 3.87 (3H, s), 5.08 (2H, s),6.7-6.9 (2H, m), 6.9-7.1 (2H, m), 7.58 (2H, brs).

Reference Example 8

Production of 4-bromo-2-(trifluoromethyl)benzonitrile

To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (1.02 g) inacetonitrile (30 ml) was added dropwise tert-butyl nitrite (0.95 ml) at0° C. The reaction mixture was stirred at the same temperature for 0.5hour. To the reaction mixture was added copper bromide (II) (1.39 g)little by little. The temperature of the reaction mixture was raised upto room temperature, and the reaction mixture was stirred further for 14hours. The reaction mixture was poured into a saturated solution ofsodium chloride, extracted with ethyl acetate, and the ethyl acetatelayer was dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) and crystallized from ethyl acetate-hexane toobtain the titled compound (1.13 g) as pale yellow oily substance.

¹H-NMR (CDCl₃) δ 7.71 (1H, d, J=8.2 Hz), 7.8-7.9 (1H, m), 7.95 (1H, s).

Reference Example 9

Production of 4-bromophthalonitrile

By using 4-aminophthalonitrile(3.14 g), the reaction and purificationwere carried out in the same manner as Reference Example 8 to obtain thetitled compound (729 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 7.68 (1H, d, J=8.4 Hz), 7.8-8.0 (2H, m).

Reference Example 10

Production of Methyl4-bromo-1-[tert-butyl(dimethyl)silyl]-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (1.87 g) produced in Reference Example 2 andtert-butyl (dimethyl)silyl chloride (1.34 g), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (1.86 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 0.57 (6H, s), 0.97 (9H, s), 2.30 (3H, s), 2.58 (3H, s),3.83 (3H, s).

Reference Example 11

Production of1-[tert-butyl(dimethyl)silyl]-4-(methoxycarbonyl)-2,5-dimethyl-1H-pyrrol-3-ylboronicAcid

By using the compound (0.95 g) produced in Reference Example 10, thereaction and purification were carried out in the same manner asReference Example 5 to obtain the titled compound (640 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 0.60 (6H, s), 1.01 (9H, s), 2.55 (3H, s), 2.59 (3H, s),3.86 (3H, s), 7.37 (2H, brs).

Reference Example 12

Production of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carbonitrile

By using 3,5-dimethyl-1H-pyrrole-2-carbonitrile (1.82 g, produced by amethod described in Synthesis, 1999, 46-48), the reaction andpurification were carried out in the same manner as Reference Example 2to obtain the titled compound (2.74 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.16 (3H, s), 2.26 (3H, s), 8.73 (1H, s).

Reference Example 13

Production of 4-bromo-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using 2,5-dimethyl-1H-pyrrole-3-carbonitrile (750 mg, produced by amethod described in J. Org. Chem., 43, 4273-4276 (1978)), the reactionand purification were carried out in the same manner as ReferenceExample 2 to obtain the titled compound (867 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.19 (3H, s), 2.38 (3H, s), 8.45 (1H, s).

Reference Example 14

Production of 1-nitro-4-[(1E)-2-nitro-1-butenyl]benzene

By using 1-nitropropane (25 ml), the reaction and purification werecarried out in the same manner as Reference Example 1 to obtain thetitled compound (9.48 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.28 (3H, t, J=7.8 Hz), 2.83 (2H, q, J=7.8 Hz), 7.51(2H, d, J=8.2 Hz), 7.76 (2H, d, J=8.2 Hz), 7.97 (1H, s).

Reference Example 15

Production of Methyl 5-methylpyridine-2-carboxylate

Under carbon monoxide atmosphere, a solution of 2-bromo-5-methylpyridine(10.0 g), triethylamine (16.7 ml), methanol (2.4 ml),1,1′-bis(diphenylphosphino)ferrocene (3.2 g) and palladium hydroxide(1.3 g) in N,N-dimethylformamide (150 ml) was stirred at 70° C. for 20hours. The solution was allowed to stand until it cooled to roomtemperature. The reaction mixture was poured into a saturated aqueoussolution of sodium chloride and extracted with ethyl acetate. The ethylacetate layer was dried over magnesium sulfate, and concentrated. Theresidue was purified by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate) and recrystallized from ethylacetate-hexane to obtain the titled compound (1.69 g) as yellowcrystals.

¹H-NMR (CDCl₃) δ2.42 (3H, s), 4.00 (3H, s), 7.63 (1H, dd, J=1.5, 8.1Hz), 8.03 (1H, d, J=8.1 Hz), 8.56 (1H, d, J=1.5 Hz).

Reference Example 16

Production of Tert-butyl 5-methylpyridin-2-ylcarbamate

A solution of 2-amino-5-methylpyridine (5.01 g) and di-tert-butyldicarbonate (11.7 ml) in 2-methyl-2-propanol (100 ml) was stirred atroom temperature for 20 hours. The reaction mixture was poured into asaturated aqueous solution of sodium chloride, and extracted with ethylacetate. The ethyl acetate layer was dried over magnesium sulfate, andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to obtain the titled compound (4.60 g) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.49 (9H, s), 2.26 (3H, s), 7.4-7.6 (1H, m), 7.84 (1H,d, J=8.4 Hz), 8.0-8.2 (2H, m).

Reference Example 17

Production of Methyl4-bromo-1-(4-cyanobenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (1.88 g) produced in Reference Example 2 and4-cyanobenzyl bromide (1.59 g), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (2.06 g) as colorless crystals.

1H-NMR (CDCl3) δ 2.13 (3H, s), 2.42 (3H, s), 3.85 (3H, s), 5.13 (2H, s),6.99 (2H, d, J=8.0 Hz), 7.63 (2H, d, J=8.0 Hz).

Reference Example 18

Production of (6-methylpyridin-3-yl)methanol

To a solution of methyl 6-methylnicotinate (2.45 g) in tetrahydrofuran(30 ml) was added slowly lithium aluminum hydride (0.62 g) at 0° C.After the temperature of the reaction mixture was elevated to roomtemperature, the reaction mixture was stirred at the same temperaturefor 2 hours. The reaction mixture was poured into saturated brine, andextracted with ethyl acetate. The ethyl acetate layer was dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) toobtain the titled compound (1.49 g) as a yellow oily substance.

¹H-NMR (CDCl₃) δ 2.51 (3H, s), 3.86 (1H, brs), 4.66 (2H, s), 7.13 (1H,d, J=8.0 Hz), 7.61 (1H, dd, J=2.2, 8.0 Hz), 7.63 (1H, d, J=2.2 Hz).

Reference Example 19

Production of 1,2-dichloro-4-((1E)-2-nitro-1-propenyl)benzene

By using 3,4-dichlorobenzaldehyde (91.44 g), the reaction andpurification were carried out in the same manner as Reference Example 1to obtain the titled compound (62.5 g) as yellow crystals.

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 7.23-7.27 (1H, m), 7.50-7.54 (2H, m),7.95 (1H, s).

Reference Example 20

Production of 3-((1E)-2-nitro-1-propenyl)benzonitrile

By using 3-cyanobenzaldehyde (21.00 g), the reaction and purificationwere carried out in the same manner as Reference Example 1 to obtain thetitled compound (16.51 g) as pale yellow crystals.

IR (KBr): ν 2232, 1520, 1327, 799, 681 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 7.55-7.75 (4H, m), 8.03 (1H, s).

Reference Example 21

Production of Ethyl4-bromo-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate

By using (3.69 g) produced in Reference Example 3 and 4-fluorobenzylbromide (1.9 ml), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (4.11 g) ascolorless crystals.

IR (KBr): ν 1694, 1512, 1271, 1138 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.2 Hz), 2.19 (3H, s), 2.34 (3H, s),4.23 (2H, q, J=7.2 Hz), 5.55 (2H, s), 6.88-7.00 (4H, m).

Reference Example 22

Production of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic Acid

A mixture of the compound (7.00 g) produced in Reference Example 3, 6Nsodium hydroxide (100 ml) and ethanol (100 ml) was heated for 3 hoursunder reflux and concentrated. The residue was cooled on a ice bath,adjusted to pH 1 by adding hydrogen chloride little by little, andextracted with ethyl acetate. The ethyl acetate layer was dried overanhydrous magnesium sulfate and concentrated to obtain the titledcompound (6.20 g) as pale brown crystals.

IR (KBr): ν 3212, 1686, 1240 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 2.32 (3H, s), 8.91 (1H, br).

Reference Example 23

Production of Benzyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate

To a mixture of the compound (6.20 g) produced in Reference Example 22,potassium hydrogencarbonate (8.5 g) and dimethylformamide (50 ml) wasadded dropwise benzyl bromide (3.45 ml). The reaction mixture wasstirred at room temperature for 14 hours, diluted with water andextracted with ethyl acetate. The ethyl acetate layer was washed with 1Nhydrochloric acid, water and saturated sodium bicabonate water,successively, dried over magnesium sulfate and concentrated. The residuewas purified by column chromatography (carrier: silicagel, eluant: ethylacetate) to obtain the titled compound (8.46 g) as colorless crystals.

IR (KBr): ν 3283, 1672, 1288 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.25 (3H, s), 2.30 (3H, s), 5.30 (2H, s), 7.32-7.41(5H, m), 8.79 (1H, br).

Reference Example 24

Production of Benzyl4-bromo-1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate

A suspension of sodium hydride (60% oil suspension, 0.58 g) indimethylformamide (10 ml) was cooled on ice bath, and to the suspensionwas added dropwise a solution of the compound (4.46 g) produced inReference Example 23 in dimethylformamide (15 ml). The reaction mixturewas stirred at the same temperature for 10 minutes. To the reactionmixture was added 4-cyanobenzyl bromide (2.84 g) and the reactionmixture was further stirred for 3 hours. The reaction mixture was pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with water, water and saturated brine, successively, dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate), andrecrystallized from ethyl acetate-hexane to obtain the titled compound(5.73 g) as colorless crystals.

IR (KBr): ν 2228, 1694, 1424, 1271, 1134, 743 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.18 (3H, s), 2.34 (3H, s), 5.20 (2H, s), 5.62 (2H,s), 6.96 (2H, d, J=8.8 Hz), 7.30-7.33 (5H, m), 7.55 (2H, d, J=8.8 Hz).

Reference Example 25

Production of 4-((1E)-2-nitro-1-propenyl)benzonitrile

By using 4-cyanobenzaldehyde (75.9 g), the reaction and purificationwere carried out in the same manner as Reference Example 1 to obtain thetitled compound (55.1 g) as pale yellow crystals.

Reference Example 26

Production of 1-bromo-4-((1E)-2-nitro-1-propenyl)benzene

By using 4-bromobenzaldehyde (50.4 g), the reaction and purificationwere carried out in the same manner as Reference Example 1 to obtain thetitled compound (33.2 g) as pale brown crystals.

Reference Example 27

Production of 4-((1E)-2-nitro-1-ethenyl)benzonitrile

To a mixture of 4-cyanobenzaldehyde (50.7 g) and nitro methane (100 g)was added n-butylamine (2.4 ml), and the reaction mixture was heated for18 hours under reflux. The reaction mixture was cooled to roomtemperature. The resulting precipitates were collected to obtain thetitled compound (21.7 g) as a brown powder.

¹H-NMR (CDCl₃) δ: 7.61 (1H, d, J=13.6 Hz), 7.66 (2H, d, J=8.4 Hz), 7.76(2H, d, J=8.4 Hz), 7.99 (1H, d, J=13.6 Hz).

Reference Example 28

Production of 2-iodomethyl-1-trityl-1H-imidazole

To a mixture of 2-hydroxymethyl-1-trityl-1H-imidazole (5.13 g),triethylamine (2.5 ml) and dichloromethane (100 ml) was addedmethanesulfonyl chloride (1.3 ml), and the reaction mixture was stirredat room temperature for 18 hours and poured into water. Thedichloromethane layer was separated, washed with saturated brine, driedover magnesium sulfate and concentrated. The residue was dissolved inacetone (100 ml), and to the reaction mixture was added sodium iodide(6.75 g). The reaction mixture was heated for 1 hour under reflux,concentrated and dissolved in a solution of ethyl acetate and 5% sodiumthiosulfate. The ethyl acetate layer was separated and washed withsaturated brine, dried over magnesium sulfate and concentrated to obtainthe titled compound (2.53 g) as colorless crystals.

IR (KBr): ν 1491, 1447, 752, 700 cm⁻¹.

¹H-NMR (CDCl₃) δ: 3.76 (2H, s), 6.69 (1H, d, J=1.6 Hz), 7.08-7.41 (16H,m).

Reference Example 29

Production of 4-bromomethyl-1-trityl-1H-imidazole

A mixture was 4-hydroxymethyl-1-trityl-1H-imidazole (3.40 g),triphenylphosphine (3.14 g) and dichloromethane (50 ml) was cooled onice bath, and to the mixture was added N-bromosuccinimide (2.14 g). Thereaction mixture was stirred at 0° C. for 2 hours. To the reactionmixture was added saturated sodium bicarbonate solution, and thedichloromethane layer was separated. The dichloromethane layer waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) to obtain the titled compound (2.00 g) ascolorless solids. The compound was unstable and thus it was used for thefollowing reaction at once.

Reference Example 30

Production of 4-iodomethyl-1-trityl-1H-1,2,3-triazole

By using 4-hydroxymethyl-1-trityl-1H-1,2,3-triazole (9.30 g), thereaction and purification were carried out in the same manner asReference Example 28 to obtain the titled compound (9.93 g) as palebrown crystals.

Reference Example 31

Production of4-bromo-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic Acid

By using the compound (2.00 g) produced in Reference Example 21, thereaction and purification were carried out in the same manner asReference Example 22 to obtain the titled compound (1.85 g) as colorlesscrystals.

IR (KBr): ν 1655, 1508, 1447, 1292, 1217, 1148 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.37 (3H, s), 5.56 (2H, s), 6.87-6.99(4H, m).

Reference Example 32

Production of Tert-butyl4-bromo-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrol-2-ylcarbamate

A mixture of the compound (1.11 g) produced in Reference Example 31,diphenylphosphoryl azide (1.17 g), triethylamine(0.71 ml) and tert-butylalcohol (15 ml) was heated for 16 hours under reflux and concentrated.The residue was dissolved in tetrahydrofuran and saturated sodiumbicarbonate water. The tetrahydrofuran layer was separated, washed withsaturated brine, dried over magnesium sulfate and concentrated. Theresidue was purified by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate) to obtain the titled compound (0.8.4 g).

IR (KBr): ν 3295, 1701, 1510, 1159 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.95 (3H, s), 2.07 (3H, s), 4.92 (2H,s), 5.50-5.70 (1H, br), 6.90-7.00 (4H, m).

Reference Example 33

Production of 3-(1-bromoethyl)pyridine

A mixture of 3-ethylpyridine (0.86 g), 2,2′-azobis(isobutyronitrile)(0.13 g), N-bromosuccinimide (1.57 g) and carbon tetrachloride (16 ml)was heated in a 90° C. oil bath for 1 hour. The reaction mixture wascooled to room temperature and insoluble matter was removed byfiltration. The filtrate was washed with water, saturated brine,successively, dried over magnesium sulfate and concentrated to obtainthe titled crude compound (0.84 g) as a colorless oily substance. Theobtained crude compound was used for the next reaction.

¹H-NMR (CDCl₃) δ: 2.06 (3H, d, J=7.0 Hz), 5.19 (1H, q, J=7.0 Hz), 7.30(1H, dd, J=8.0, 4.8 Hz), 7.79 (1H, dt, J=8.0, 2.0 Hz), 8.53 (1H, dd,J=4.8, 2.0 Hz), 8.65-8.67 (1H, m).

Example 1

Production of Ethyl2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

A suspension of powdery potassium hydroxide (0.15 g) in tetrahydrofuran(5 ml) was cooled in an ice bath, and to the suspension was addeddropwise ethyl acetoacetate (1.0 ml). The mixture was stirred at thesame temperature for 15 minutes, and to the mixture was added thecompound (0.56 g) produced in Reference Example 1. The reaction mixturewas stirred at room temperature for 3 hours, poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried over magnesium sulfate and concentrated. To theresidue were added methanol (16 ml), water (1.2 ml) and concentratedhydrochloric acid (0.2 ml) and the reaction mixture was heated for 2hours under reflux. The reaction mixture was concentrated, diluted withsaturated sodium bicarbonate water and extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant:. hexane-ethyl acetate) toobtain the titled compound (0.32 g) as yellow crystals.

¹H-NMR (CDCl₃) δ: 1.11 (3H, t, J=7.2 Hz), 2.14 (3H, s), 2.52 (3H, s),4.12 (2H, q, J=7.2 Hz), 7.41 (2H, d, J=8.7 Hz), 8.20 (2H, d, J=8.7 Hz),8.23 (1H, brs).

IR (KBr): ν 2976, 2930, 1684, 1595, 1516 cm⁻¹.

Example 2

Production of Ethyl1,2,5-trimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

A suspension of sodium hydride (60% oil suspension, 32 mg) intetrahydrofuran (1 ml) was cooled in an ice bath, and to the suspensionwas added dropwise a solution of the compound (230 mg) produced inExample 1 in tetrahydrofuran (1 ml). The reaction mixture was stirred atthe same temperature for 1 hour. To the reaction mixture was addedmethyl iodide (0.05 ml) and the reaction mixture was further stirred for3 hours. The reaction mixture was poured into saturated brine andextracted with ethyl acetate. The ethyl acetate layer was dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) andrecrystallized from ethyl acetate-hexane to obtain the titled compound(0.09 g) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.04 (3H, t, J=7.2 Hz), 2.11 (3H, s), 2.56 (3H, s),3.49 (3H, s), 4.07 (2H, q, J=7.2 Hz), 7.37 (2H, d, J=8.7 Hz), 8.19 (2H,d, J=8.7 Hz).

IR (KBr): ν 2978, 2934, 2905, 2693, 1597, 1537, 1512 cm⁻¹.

Example 3

Production of Ethyl1-ethyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.29 g) produced in Example 1 and ethyl iodide(0.09 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (180 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 1.03 (3H, t, J=7.0 Hz), 1.32 (3H, t, J=7.0 Hz), 2.13(3H, s), 2.58 (3H, s), 3.92 (2H, q, J=7.0 Hz), 4.07 (2H, q, J=7.0 Hz),7.3-7.5 (2H, m), 8.1-8.3 (2H, m).

IR (KBr): ν2982, 2936, 1694, 1597, 1514, 1345 cm⁻¹.

Example 4

Production of Ethyl1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (4.87 g) produced in Example 1 and benzyl bromide(2.0 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (5.3 g) as yellowcrystals.

¹H-NMR (CDCl₃) δ 1.03 (3H, t, J=7.2 Hz), 2.05 (3H, s), 2.51 (3H, s),4.10 (2H, q, J=7.2 Hz), 5.13 (2H, s), 6.9-7.1 (2H, m), 7.2-7.4 (3H, m),7.42 (2H, d, J=8.8 Hz), 8.21 (2H, d, J=8.8 Hz).

IR (KBr): ν 2978, 2921, 1694, 1597, 1514, 1345 cm⁻¹.

Example 5

Production of Ethyl1-butyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.29 g) produced in Example 1 and butyl iodide(0.13 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (132 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 0.99 (3H, t, J=7.2 Hz), 1.03 (3H, t, J=7.4 Hz), 1.3-1.5(2H, m), 1.6-1.8 (2H, m), 2.12 (3H, s), 2.56 (3H, s), 3.83 (2H, t, J=7.8Hz), 4.07 (2H, q, J=7.4 Hz), 7.37 (2H, d, J=8.8 Hz), 8.19 (2H, d, J=8.8Hz).

IR (KBr): ν 2961, 2934, 1696, 1597, 1514, 1343 cm⁻¹.

Example 6

Production of Ethyl1-(4-hydroxybutyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.32 g) produced in Example 1 and2-(4-iodobutoxy)tetrahydropyran (0.32 g), the reaction and purificationwere carried out in the same manner as Example 2 to obtain a crudeproduct (0.16 g) containing ethyl2,5-dimethyl-4-(4-nitrophenyl)-1-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-1H-pyrrole-3-carboxylate.To the crude product were added methanol (3 ml) and 1 N hydrochloricacid (1 ml), and the mixture was stirred at room temperature for 2hours. The reaction mixture was neutralized by the addition of saturatedsodium bicarbonate and extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried over magnesium sulfated andconcentrated. The residue was purified by recrystallization (ethylacetate-hexane) to obtain the titled compound (62 mg) as brown crystals.

¹H-NMR (CDCl₃) δ 1.03 (3H, t, J=7.4 Hz), 1.5-1.9 (4H, m), 2.13 (3H, s),2.57 (3H, s), 3.6-3.8 (2H, m), 3.8-4.0 (2H, m), 4.07 (2H, q, J=7.0 Hz),7.37 (2H, d, J=8.8 Hz), 8.19 (2H, d, J=8.8 Hz).

IR (KBr): ν 3480, 2980, 2938, 2872, 1694, 1597, 1514, 1343 cm³¹ ¹.

Example 7

Production of Ethyl2,5-dimethyl-1-(methylsulfonyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.14 g) produced in Example 1 and methanesulfonylchloride (0.05 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (115 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 0.97 (3H, t, J=7.2 Hz), 2.28 (3H, s), 2.80 (3H, s),3.26 (3H, s), 4.05 (2H, q, J=7.2 Hz), 7.3-7.5 (2H, m), 8.2-8.3 (2H, m).

IR (KBr): ν 2982, 2934, 1709, 1599, 1373, 1348 cm⁻¹.

Example 8

Production of Ethyl1-benzoyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.14 g) produced in Example 1 and benzoylchloride (0.06 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (129 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.2 Hz), 1.98 (3H, s), 2.39 (3H, s),4.11 (2H, q, J=7.2 Hz), 7.4-7.5 (2H, m), 7.5-7.6 (2H, m), 7.6-7.9 (3H,m), 8.1-8.3 (2H, m).

IR (KBr): ν 2982, 1705, 1599, 1516, 1346, 1329 cm⁻¹.

Example 9

Production of Ethyl2,5-dimethyl-4-(4-nitrophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

By using the compound (0.14 g) produced in Example 1 and benzenesulfonylchloride, the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (111 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 0.94 (3H, t, J=7.2 Hz), 2.29 (3H, s), 2.77 (3H, s),4.02 (2H, q, J=7.2 Hz), 7.2-7.4 (2H, m), 7.5-7.8 (3H, m), 7.8-7.9 (2H,m), 8.1-8.3 (2H, m).

IR (KBr): ν 2982, 2938, 1709, 1599, 1518, 1375, 1346 cm⁻¹.

Example 10

Production of Ethyl2,5-dimethyl-4-(4-nitrophenyl)-1-(2-phenylethyl)-1H-pyrrole-3-carboxylate

By using the compound (0.15 g) produced in Example 1 and phenethyliodide (0.12 ml), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (16 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 1.04 (3H, t, J=7.2 Hz), 1.92 (3H, s), 2.51 (3H, s),2.95 (2H, t, J=7.4 Hz), 4.0-4.2 (4H, m), 7.0-7.2 (2H, m), 7.2-7.4 (5H,m), 8.19 (2H, d, J=8.8 Hz).

IR (KBr): ν 3027, 2980, 2928, 1696, 1597, 1518, 1375, 1346 cm⁻¹.

Example 11

Production of Methyl4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and3-cyanophenylboronic acid (0.16 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (138 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.11 (3H, s), 2.52 (3H, s), 3.63 (3H, s), 7.4-7.6 (4H,m), 8.04 (1H, s).

IR (KBr): ν 2951, 2226, 1674, 1606, 1446 cm⁻¹.

Example 12

Production of Methyl1-benzyl-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (84 mg) produced in Example 11 and benzyl bromide(0.05 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (51 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 2.01 (3H, s), 2.50 (3H, s), 3.60 (3H, s), 5.12 (2H, s),6.9-7.0 (2H, m), 7.2-7.6 (7H, m).

IR (KBr): ν 3065, 3032, 2988, 2948, 2228, 1699, 1534 cm⁻¹.

Example 13

Production of 2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylicAcid

The compound (390 mg) produced in Example 1 was added to concentratedsulfuric acid (1.0 ml) little by little, and the mixture was stirred atroom temperature for 0.5 hour. The reaction mixture was added dropwiseto ice water and extracted with ethyl acetate. The ethyl acetate layerwas dried over magnesium sulfate and concentrated. The residue wasrecrystallized from ethyl acetate to obtain the titled compound (202 mg)as yellow crystals.

¹H-NMR (DMSO-d₆) δ2.09 (3H, s), 2.41 (3H, s), 7.44 (2H, d, J=7.6 Hz),8.15 (2H, d, J=7.6 Hz), 11.27 (1H, s).

IR (KBr): ν 3368, 3325, 3304, 1667 cm¹.

Example 14

Production of Methyl4-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

To a mixture of the compound (0.23 g) produced in Reference Example2,4-fluorophenylboronic acid (0.15 g), tetrakis(triphenylphosphine)palladium (0.06 g) and anhydrous sodium carbonate(0.32 g) were added dimethylformamide (8 ml) and water (2 ml) and themixture was heated at 130° C. for 20 hours and cooled to roomtemperature. To the resulting reaction mixture was added water andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The resulting crude product was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) toobtain the titled compound (138 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.09 (3H, s), 2.51 (3H, s), 3.62 (3H, s), 6.9-7.1 (2H,m), 7.1-7.3 (2H, m), 7.99 (1H, s).

IR (KBr): ν 3287, 3096, 2994, 2949, 1667 cm⁻¹.

Example 15

Production Methyl of4-(4-acetylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-acetylphenylboronic acid (0.18 g), the reaction and purification werecarried out in the same manner as

Example 14 to obtain the titled compound (146 mg) as pale yellowcrystals.

¹H-NMR (CDCl₃) δ 2.13 (3H, s), 2.52 (3H, s), 2.62 (3H, s), 3.63 (3H, s),7.34 (2H, d, J=8.4 Hz), 7.94 (2H, d, J=8.4 Hz), 8.23 (1H, s).

IR (KBr): ν 3306, 3119, 2949, 1682 cm⁻¹.

Example 16

Production of Methyl4-(4-(methoxycarbonyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-(methoxycarbonyl)phenylboronic acid (0.20 g), the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (77 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.13 (3H, s), 2.52 (3H, s), 3.61 (3H, s), 3.92 (3H, s),7.35 (2H, d, J=8.0 Hz), 7.59 (2H, d, J=8.4 Hz), 8.01 (1H, s).

IR (KBr): ν 3320, 2951, 1716, 1696 cm⁻¹.

Example 17

Production of Methyl4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using-the compound (0.23 g) produced in Reference Example 2 and4-cyanophenylboronic acid (0.16 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (82 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.13 (3H, s), 2.52 (3H, s), 3.63 (3H, s), 7.35 (2H, d,J=8.0 Hz), 7.62 (2H, d, J=8.4 Hz), 8.14 (1H, s).

IR (KBr): ν 3296, 2990, 2951, 2226, 1674 cm⁻¹.

Example 18

Production of Methyl2,5-dimethyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-(trifluoromethyl)phenylboronic acid (0.21 g), the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (108 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.12 (3H, s), 2.52 (3H, s), 3.63 (3H, s), 7.35 (2H, d,J=8.0 Hz), 7.59 (2H, d, J=8.0 Hz), 8.0 (1H, s).

IR (KBr): ν 3287, 2949, 2862, 2714, 1669 cm⁻¹.

Example 19

Production of Methyl4-(4-formylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-formylphenylboronic acid (0.21 g), the reaction and purification werecarried out in the same manner as

Example 14 to obtain the titled compound (125 mg) as pale yellowcrystals.

¹H-NMR (CDCl₃) δ 2.15 (3H, s), 2.53 (3H, s), 3.63 (3H, s), 7.41 (2H, dd,J=6.6, 1.8 Hz), 7.86 (2H, dd, J=6.6, 1.8 Hz), 8.11 (1H, s), 10.02 (1H,s).

IR (KBr): ν 2948, 2841, 1695, 1682, 1447 cm⁻¹.

Example 20

Production of Methyl1-benzyl-4-(4-formylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (86 mg) produced in Example 19 and benzyl bromide(0.05 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (46 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 2.06 (3H, s), 2.50 (3H, s), 3.60 (3H, s), 5.13 (2H, s),6.9-7.0 (2H, m), 7.2-7.6 (5H, m), 7.87 (2H, d, J=8.8 Hz), 10.03 (1H, s).

IR (KBr): ν 3030, 2948, 1696, 1605, 1537, 1439 cm⁻¹.

Example 21

Production of Methyl2,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-(methylsulfonyl)phenylboronic acid (0.22 g), the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (198 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.13 (3H, s), 2.52 (3H, s), 3.10 (3H, s), 3.65 (3H, s),7.44 (2H, d, J=8.0 Hz), 7.89 (2H, d, J=8.0 Hz), 8.16 (1H, s).

IR (KBr): ν 3287, 2949, 2862, 2714, 1669 cm⁻¹.

Example 22

Production of 4-(4-(methoxycarbonyl)-2,5-dimethyl-1H-pyrrol-3-yl)benzoicAcid

By using the compound (0.23 g) produced in Reference Example 2 and4-(dihydroxyboryl)benzoic acid (0.18 g), the reaction and purificationwere carried out in the same manner as Example 14 to obtain the titledcompound (118 mg) as pale yellow crystals.

¹H-NMR (DMSO-d₆) δ 2.06 (3H, s), 2.40 (3H, s), 3.51 (3H, s), 7.26 (2H,d, J=8.0 Hz), 7.87 (2H, d, J=8.0 Hz), 11.25 (1H, s).

IR (KBr): ν 3296, 3252, 1682, 1669 cm⁻¹.

Example 23

Production of Methyl4-(4-(aminocarbonyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-(aminocarbonyl)phenylboronic acid (0.17 g), the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (150 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.12 (3H, s), 2.49 (3H, s), 3.60 (3H, s), 6.18 (1H,brs), 7.04 (1H, brs), 7.30 (2H, d, J=8.0 Hz), 7.83 (2H, d, J=8.0 Hz),10.28 (1H, s).

IR (KBr): ν 3103, 2955, 1669, 1609 cm⁻¹.

Example 24

Production of Methyl4-(3-nitrophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.46 g) produced in Reference Example 2 and3-nitrophenylboronic acid (0.34 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (240 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ2.14 (3H, s), 2.54 (3H, s), 3.63 (3H, s), 7.5-7.7 (2H,m), 8.03 (1H, s), 8.1-8.2 (2H, m).

Example 25

Production of Methyl4-(3-aminophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and3-aminophenylboronic acid (0.16 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (77 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.11 (3H, s), 2.50 (3H, s), 3.63 (3H, s), 6.5-6.7 (3H,m), 7.0-7.2 (1H, m), 7.94 (1H, s).

IR (KBr): ν 3306, 3020, 2948, 1682 cm⁻¹.

Example 26

Production of Methyl2,5-dimethyl-4-(4-(methylthio)phenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-(methylthio)phenylboronic acid (0.17 g), the reaction and purificationwere carried out in the same manner as Example 14 to obtain the titledcompound (172 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.11 (3H, s), 2.50 (6H, s), 3.63 (3H, s), 7.1-7.4 (4H,m), 7.96 (1H, s).

IR (KBr): ν 3310, 2988, 2946, 2920, 1669 cm⁻¹.

Example 27

Production of Methyl4-(1-benzofuran-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and1-benzofuran-2-ylboronic acid (0.17 g), the reaction and purificationwere carried out in the same manner as Example 14 to obtain the titledcompound (78 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.33 (3H, s), 2.51 (3H, s), 3.71 (3H, s), 6.76 (1H, s),7.2-7.3 (2H, m), 7.4-7.6 (2H, m), 8.06 (1H, s).

IR (KBr): ν 3310, 2949, 2924, 1682 cm⁻¹.

Example 28

Production of Methyl2,5-dimethyl-4-(2-naphthyl)-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and2-naphthylboronic acid (0.18 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (91 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.16 (3H, s), 2.54 (3H, s), 3.58 (3H, s), 7.1-7.3 (3H,m), 7.6.6 (1H, s), 7.7-7.9 (3H, m), 7.98 (1H, s).

IR (KBr): ν 303, 3052, 2947, 1682 cm⁻¹.

Example 29

Production of Methyl2,5-dimethyl-4-(3-pyridinyl)-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and3-pyridinyldiethylborane (0.15 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (99 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.13 (3H, s), 2.53 (3H, s), 3.62 (3H, s), 7.2-7.4 (1H,m), 7.5-7.7 (1H, m), 8.4-8.5 (2H, m), 8.57 (1H, s).

IR (KBr): ν 3287, 2948, 2743, 1693 cm⁻¹.

Example 30

Production of Methyl 4-(3-furyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and3-furylboronic acid (0.12 g), the reaction and purification were carriedout in the same manner as Example 14 to obtain the titled compound (112mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.18 (3H, s), 2.50 (3H, s), 3.71 (3H, s), 6.47 (1H, dd,J=0.8, 1.8 Hz), 7.38 (1H, d, J=0.8 Hz), 7.42 (1H, d, J=1.8 Hz), 7.94(1H, s).

IR (KBr): ν 3294, 2947, 2714, 1669 cm⁻¹.

Example 31

Production of Methyl 2,5-dimethyl-4-(3-thienyl)-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and3-thienylboronic acid (0.13 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (109 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.17 (3H, s), 2.51 (3H, s), 3.67 (3H, s), 7.06 (2H, d,J=4.4 Hz), 7.2-7.3 (1H, m), 7.93 (1H, s).

IR (KBr): ν 3306, 2947, 2922, 1682 cm⁻¹.

Example 32

Production of Methyl4-(2,4-dimethoxy-5-pyrimidinyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and2,4-dimethoxy-5-pyrimidinylboronic acid (0.19 g), the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (24 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.10 (3H, s), 2.52 (3H, s), 3.61 (3H, s), 3.94 (3H, s),4.03 (3H, s), 8.02 (1H, s), 8.10 (1H, s)

IR (KBr): ν 3277, 2951, 1682, 1591 cm⁻¹.

Example 33

Production of Methyl 4-(2-furyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and2-furylboronic acid (0.19 g), the reaction and purification were carriedout in the same manner as Example 14 to obtain the titled-compound (24mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.24 (3H, s), 2.48 (3H, s), 3.72 (3H, s), 6.3-6.4 (1H,m), 6.4-6.5 (1H, m), 7.4-7.5 (1H, m), 8.00 (1H, s).

IR (KBr): ν 3303, 3160, 2949, 1682 cm⁻¹.

Example 34

Production of Methyl4-(4-hydroxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-hydroxyphenylboronic acid (0.14 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (151 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.11 (3H, s), 2.51 (3H, s), 3.63 (3H, s), 4.93 (1H, s),6.80 (2H, d, J=8.8 Hz), 7.11 (2H, d, J=8.8 Hz), 7.87 (1H, s).

IR (KBr): ν 3285, 2949, 1667, 1448 cm⁻¹.

Example 35

Production of Methyl4-(4-(hydroxymethyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and4-hydroxyphenylboronic acid (0.15 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (89 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.12 (3H, s), 2.51 (3H, s), 3.62 (3H, s), 4.6-4.8 (3H,m), 7.25 (2H, d, J=8.0 Hz), 7.35 (2H, d, J=8.0 Hz), 7.97 (1H, s).

IR (KBr): ν 3248, 2920, 2860, 1684, 1539 cm⁻¹.

Example 36

Production of Methyl4-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and3,5-bis(trifluoromethyl)phenylboronic acid (0.26 g), the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (222 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.15 (3H, s), 2.54 (3H, s), 3.60 (3H, s), 7.70 (2H, s),7.75 (1H, s), 8.07 (1H, s).

IR (KBr): ν 3366, 2953, 1680, 1539 cm⁻¹.

Example 37

Production of Methyl4-(3,5-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and3,5-dichlorophenylboronic acid (0.19 g), the reaction and purificationwere carried out in the same manner as Example 14 to obtain the titledcompound (262 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.12 (3H, s), 2.51 (3H, s), 3.64 (3H, s), 7.1-7.2 (2H,m), 7.2-7.3 (1H, m), 7.99 (1H, s).

IR (KBr): ν 3299, 2948, 1682, 1588 cm⁻¹.

Example 38

Production of Methyl4-(3,4-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.55 g) produced in Reference Example 2 and3,4-dichlorophenylboronic acid (0.38 g), the reaction and purificationwere carried out in the same manner as Example 14 to obtain the titledcompound (393 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.11 (3H, s), 2.50 (3H, s), 3.64 (3H, s), 7.08 (1H, dd,J=1.8, 8.0 Hz), 7.33 (1H, d, J=1.8 Hz), 7.39 (1H, d, J=8.0 Hz), 8.04(1H, s).

IR (KBr): ν 3303, 2949, 2922, 1674 cm⁻¹.

Example 39

Production of Methyl1-benzyl-2,5-dimethyl-4-(3-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (152 mg) produced in Example 24 and benzyl bromide(0.14 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (126 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 2.04 (3H, s), 2.51 (3H, s), 3.60 (3H, s), 5.14 (2H, s),6.95 (2H, d, J=4.6 Hz), 7.2-7.4 (3H, m), 7.4-7.6 (2H, m), 8.1-8.2 (2H,m).

IR (KBr): ν 3063, 2948, 1699, 1526 cm⁻¹.

Example 40

Production of Methyl1-benzyl-4-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (66 mg) produced

Example 14 and benzyl bromide (0.05 ml), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (23 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.01 (3H, s), 2.49 (3H, s), 3.60 (3H, s), 5.11 (2H, s),6.9-7.0 (2H, m), 7.0-7.1 (2H, m), 7.2-7.4 (5H, m).

IR (KBr): ν 3031, 2946, 1696, 1537 cm⁻¹.

Example 41

Production of Methyl1-benzyl-2,5-dimethyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate

By using the compound (66 mg) produced in Example 18 and benzyl bromide(0.05 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (15 mg) as colorlessoily substance.

¹H-NMR (CDCl₃) δ 2.03 (3H, s), 2.50 (3H, s), 3.60 (3H, s), 5.12 (2H, s),6.9-7.0 (2H, m), 7.2-7.5 (5H, m), 7.5-7.7 (2H, m).

Example 42

Production of Methyl1-benzyl-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (176 mg) produced in Example 17 and benzyl bromide(0.14 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (141 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 2.03 (3H, s), 2.50 (3H, s), 3.61 (3H, s), 5.13 (2H, s),6.94 (2H, d, J=4.4 Hz), 7.2-7.4 (5H, m), 7.63 (2H, d, J=4.4 Hz).

IR (KBr): ν 3031, 2948, 2224, 1699 cm⁻¹.

Example 43

Production of Methyl1-benzyl-4-(3,5-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (150 mg) produced in Example 37 and benzyl bromide(0.10 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (170 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 2.02 (3H, s), 2.48 (3H, s), 3.63 (3H, s), 5.11 (2H, s),6.8-7.0 (2H, m), 7.2-7.4 (4H, m), 8.2-8.4 (.2H, m).

IR (KBr): ν 3065, 3031, 2946, 1700 cm⁻¹.

Example 44

Production of (2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrol-3-yl)methanol

The solution of the compound (290 mg) produced in Example 1 in toluene(8 ml) was cooled on an ice bath and to the solution was added dropwisea solution of 1 N diisobutyl aluminum hydride in toluene solution (2.0ml). This mixture was stirred at room temperature for 1 hour, and thereaction mixture was then poured into water and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, driedover magnesium sulfate and concentrated. The residue was purified bycolumn chromatography (carrier: silicagel, eluant: hexane-ethyl acetate)to obtain the titled compound (0.12 g) as red crystals.

¹H-NMR (CDCl₃) δ 2.30 (3H, s), 2.32 (3H, s), 4.48 (2H, d, J=3.6 Hz),7.5-7.7 (2H, m), 7.86 (1H, s), 8.2-8.3 (2H, m).

IR (KBr): ν 3240, 2868, 1593, 1507 cm⁻¹.

Example 45

Production of(1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrol-3-yl)methanol

By using the compound (300 mg) produced in Example 4 and a solution of1N diisobutyl aluminum hydride in toluene (1.6 ml), the reaction andpurification were carried out in the same manner as Example 44 to obtainthe titled compound (136 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 2.21 (3H, s), 2.25 (3H, s), 4.52 (2H, d, J=4.8 Hz),5.11 (2H, s), 6.9-7.0 (2H, m), 7.2-7.4 (3H, m), 7.60 (2H, d, J=8.8 Hz),8.25 (2H, d, J=8.8 Hz).

IR (KBr): ν 3261, 2920, 2867, 1593 cm⁻¹.

Example 46

Production of1-benzyl-3-(methoxymethyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole

To a solution of the compound (230 mg) produced in Example 45 intetrahydrofuran (1 ml) was added sodium hydride (60% oil suspension, 20mg) at room temperature. The reaction mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added methyl iodide(0.032 ml) and the reaction mixture was further stirred at 50° C. for 3hours. The reaction mixture was poured into saturated brine andextracted with ethyl acetate. The ethyl acetate layer was dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) andrecrystallized from ethyl acetate-hexane to obtain the titled compound(78 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 2.23 (3H, s), 3.37 (3H, s), 4.21 (2H, s),5.10 (2H, s), 6.9-7.0 (2H, m), 7.2-7.4 (3H, m), 7.5-7.6 (2H, m), 8.2-8.3(2H, m).

IR (KBr): ν 3069, 2984, 5806, 1593 cm⁻¹.

Example 47

Production of1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylic Acid

By using the compound (86 mg) produced in Example 4 and concentratedsulfuric acid (1.0 ml), the reaction and purification were carried outin the same manner as Example 13 to obtain the titled compound (202 mg)as yellow crystals.

¹H-NMR (CDCl₃) δ 2.04 (3H, s), 2.51 (3H, s), 5.13 (2H, s), 6.95 (2H, d,J=8.0 Hz), 7.2-7.5 (5H, m), 8.19 (2H, d, J=8.8 Hz),

IR (KBr): ν 2851, 2585, 1661, 1599 cm⁻¹.

Example 48

Production of Ethyl1-(cyclohexylmethyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (170 mg) produced in Example 1 and cyclohexylbromide (0.14 ml), the reaction and purification were carried out in thesame manner as Example to obtain the titled compound (146 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 0.9-1.4 (5H, m), 1.02 (3H, t, J=7.0 Hz), 1.6-1.9 (6H,m), 2.10 (3H, s), 2.54 (3H, s), 3.66 (2H, d, J=7.0 Hz), 4.06 (2H, q,J=7.0 Hz), 7.37 (2H, d, J=8.8 Hz), 8.19 (2H, d, J=8.8 Hz).

IR (KBr): ν 2978, 2928, 2851, 1696 cm⁻¹.

Example 49

Production of Ethyl2,5-dimethyl-1-(2-methylbenzyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and 2-methylbenzylbromide (0.067 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (59 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.07 (3H, t, J=7.0 Hz), 2.01 (3H, s), 2.40 (3H, s),2.49 (3H, s), 4.11 (2H, q, J=7.0 Hz), 5.03 (2H, s), 6.33 (1H, d, J=6.6Hz), 7.0-7.3 (3H, m), 7.42 (2H, d, J=8.4 Hz), 8.21 (2H, d, J=8.4 Hz).

IR (KBr): ν 2984, 2943, 1696, 1597 cm⁻¹.

Example 50

Production of Ethyl2,5-dimethyl-1-(3-methylbenzyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and 3-methylbenzylbromide (0.068 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (65 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.04 (3H, s), 2.34 (3H, s),2.51 (3H, s), 4.09 (2H, q, J=7.0 Hz), 5.08 (2H, s), 6.72 (1H, d, J=8.4Hz), 6.80 (1H, s), 7.09 (1H, d, J=7.6 Hz), 7.11 (1H, d, J=7.8 Hz), 7.42(2H, d, J=8.8 Hz), 8.20 (2H, d, J=8.8 Hz).

IR (KBr): ν 2982, 2905, 1696, 1597 cm⁻¹.

Example 51

Production of Ethyl2,5-dimethyl-1-(4-methylbenzyl)-4-(-4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and 4-methylbenzylbromide (0.092 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (67 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.05 (3H, t, J=7.4 Hz), 2.04 (3H, s), 2.34 (3H, s),2.51 (3H, s), 4.09 (2H, q, J=7.4 Hz), 5.08 (2H, s), 6.72 (2H, d, J=8.0Hz), 7.15 (2H, d, J=8.0 Hz), 7.41 (2H, d, J=8.8 Hz), 8.20 (2H, d, J=8.8Hz).

IR (KBr): ν 2980, 2926, 2868, 1696 cm⁻¹.

Example 52

Production of Ethyl1-(2-fluorobenzyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and 2-fluorobenzylbromide (0.063 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (47 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.05 (3H, s), 2.51 (3H, s),4.10 (2H, q, J=7.0 Hz), 5.16 (2H, s), 6.4-6.6 (1H, m), 7.0-7.2 (2H, m),7.2-7.4 (1H, m), 7.3-7.5 (2H, m), 8.1-8.3 (2H, m).

IR (KBr): ν 3065, 2982, 2936, 1699 cm⁻¹.

Example 53

Production of Ethyl1-(4-methoxybenzyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and 4-methoxybenzylchloride (0.068 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (14 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.05 (3H, t, J=7.0 Hz), 2.05 (3H, 5), 2.52 (3H, s),3.80 (3H, s), 4.09 (2H, q, J=7.0 Hz), 5.06 (2H, s), 6.88 (4H, s), 7.41(2H, d, J=8.8 Hz), 8.20 (2H, d, J=8.8 Hz).

IR (KBr): ν 2948, 1696, 1595, 1514 cm⁻¹.

Example 54

Production of Ethyl2,5-dimethyl-4-(4-nitrophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and4-(trifluoromethyl)benzyl bromide (0.12 g), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (80 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.03 (3H, s), 2.50 (3H, s),4.10 (2H, q, J=7.0 Hz), 5.18 (2H, s), 7.07 (2H, d, J=8.0 Hz), 7.41 (2H,d, J=8.8 Hz), 7.62 (2H, d, J=8.0 Hz), 8.21 (2H, d, J=8.8 Hz).

IR (KBr): ν 2984, 2944, 1696, 1597 cm⁻¹.

Example 55

Production of Ethyl1-(4-cyanobenzyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and 4-cyanobenzylbromide (0.10 g), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (94 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.02 (3H, s), 2.49 (3H, s),4.10 (2H, q, J=7.0 Hz), 5.18 (2H, s), 7.06 (2H, d, J=8.8 Hz), 7.41 (2H,d, J=8.8 Hz), 7.66 (2H, d, J=8.8 Hz), 8.22 (2H, d, J=8.8 Hz).

IR (KBr): ν 2984, 2493,2230, 1696 cm⁻¹.

Example 56

Production of Ethyl1-(4-chlorobenzyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and 4-chlorobenzylbromide (0.11 g), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (94 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.02 (3H, s), 2.50 (3H, s),4.10 (2H, q, J=7.0 Hz), 5.09 (2H, s), 6.89 (2H, d, J=8.8 Hz), 7.32 (2H,d, J=8.8 Hz), 7.41 (2H, d, J=8.8 Hz), 8.21 (2H, d, J=8.8 Hz).

IR (KBr): ν 2978, 2945, 1696, 1597 cm⁻¹.

Example 57

Production of Ethyl2,5-dimethyl-1-(4-(methylsulfonyl)benzyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and4-(methylsulfonyl)benzyl bromide (0.17 g), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (16 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.02 (3H, s), 2.50 (3H, s),3.08 (3H, s), 4.10 (2H, q, J=7.0 Hz), 5.22 (2H, s), 7.16 (2H, d, J=8.8Hz), 7.42 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 8.22 (2H, d, J=8.8Hz).

IR (KBr): ν 2990, 1696, 1597, 1516 cm⁻¹.

Example 58

Production of Ethyl1(1,1′-biphenyl-4-ylmethyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and4-(bromomethyl)-1,1′-biphenyl (0.17 g), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (79 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.08 (3H, s), 2.55 (3H, s),4.10 (2H, q, J=7.0 Hz), 5.17 (2H, s), 7.03 (2H, d, J=8.4 Hz), 7.3-7.5(5H, m), 7.5-7.7 (4H, m), 8.21 (2H, d, J=8.4 Hz).

IR (KBr): ν 2984, 2943, 1696, 1597 cm⁻¹.

Example 59

Production of Ethyl3,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

By using the compound (0.98 g) produced in Reference Example 3 and4-nitrophenylboronic acid (0.67 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (506 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.39 (3H, t, J=7.0 Hz), 2.31 (3H, s), 2.32 (3H, s),4.35 (2H, q, J=7.0 Hz), 7.40 (2H, d, J=8.8 Hz), 8.27 (2H, d, J=8.8 Hz),8.96 (1H, s).

IR (KBr): ν 3285, 2992, 1651, 1595 cm⁻¹.

Example 60

Production of Ethyl1-benzyl-3,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

By using the compound (141 mg) produced in Example 59 and benzyl bromide(0.10 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (103 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 1.29 (3H, t, J=7.0 Hz), 2.15 (3H, s), 2.31 (3H, s),4.26 (2H, q, J=7.0 Hz), 5.65 (2H, s), 6.9-7.1 (2H, m), 7.2-7.5 (5H, m),8.2-8.4 (2H, m).

IR (KBr): ν 3065, 2984, 2932, 1690 cm⁻¹.

Example 61

Production of Methyl1-benzyl-4-(3,4-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (208 mg) produced in Example 38 and benzyl bromide(0.13 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (156 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 2.02 (3H, s), 2.49 (3H, s), 3.62 (3H, s), 5.11 (2H, s),6.8-7.0 (2H, m), 7.0-7.2 (1H, m), 7.2-7.5 (5H, m).

IR (KBr): ν 3031, 2986, 2911, 1699 cm⁻¹.

Example 62

Production of Methyl4-(3,4-dichlorophenyl)-1-((2,4-difluorophenyl)sulfonyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 38 and2,4-difluorobenzenesulfonyl chloride (72 mg), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (15 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.22 (3H, s), 2.66 (3H, s), 3.57 (3H, s), 6.9-7.1 (4H,m), 7.2-7.5 (1H, m), 8.0-8.2 (1H, m).

IR (KBr): ν 2947, 1713, 1603, 1435 cm⁻¹.

Example 63

Production of Methyl4-(3,4-dichlorophenyl)-2,5-dimethyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylate

By using the compound (130 mg) produced in Example 38 andmethanesulfonyl chloride (0.041 ml), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (114 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.27 (3H, s), 2.77 (3H, s), 3.23 (3H, s), 3.60 (3H, s),7.01 (1H, dd, J=1.8, 8.4 Hz), 7.27 (1H, d, J=1.8 Hz), 7.44 (1H, d, J=8.4Hz),

IR (KBr): ν 3011, 2934, 1713, 1549 cm⁻¹.

Example 64

Production of Ethyl1-((3,5-dimethyl-4-isoxazolyl)methyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and4-(bromomethyl)-3,5-dimethylisoxazole (95 mg), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (101 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.03 (3H, t, J=7.2 Hz), 2.01 (3H, s), 2.04 (3H, s),2.12 (3H, s), 2.53 (3H, s), 4.07 (2H, q, J=7.2 Hz), 4.85 (2H, s), 7.36(2H, d, J=8.4 Hz), 8.21 (2H, d, J=8.4 Hz)

IR (KBr): ν 2984, 2932, 1696, 1597 cm⁻¹.

Example 65

Production of Ethyl1-(4-fluorobenzyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (120 mg) produced in Example 1 and 4-fluorobenzylbromide (0.063 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (132 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.2 Hz), 2.04 (3H, s), 2.51 (3H, s),4.09 (2H, q, J=7.2 Hz), 5.10 (2H, s), 6.8-7.0 (2H, m), 7.0-7.2 (2H, m),7.41 (2H, d, J=8.7 Hz), 8.21 .(2H, d, J=8.7 Hz).

IR (KBr): ν 2980, 2942, 1696, 1512 cm⁻¹.

Example 66

Production of Ethyl2,5-dimethyl-4-(4-nitrophenyl)-1-(4-pyridinylmethyl)-1H-pyrrole-3-carboxylate

To a solution of 4-(chloromethyl)pyridine hydrochloride (0.35 g) inN,N-dimethylformamide (3 ml) was added sodium hydride (60% oilsuspension, 20 mg) at room temperature. The reaction mixture was stirredat room temperature for 1 hour. To the reaction mixture was added thecompound (230 mg) produced in Example 1 and the reaction mixture wasfurther stirred at room temperature for 14 hours.

The reaction mixture was poured into saturated brine and extracted withethyl acetate. The ethyl acetate layer was dried over magnesium sulfateand concentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate), and recrystallizedfrom ethyl acetate-hexane to obtain the titled compound (80 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 1.07 (3H, t, J=6.8 Hz), 2.04 (3H, s), 2.51 (3H, s),4.09 (2H, q, J=6.8 Hz), 5.10 (2H, s), 6.8-7.0 (2H, m), 7.0-7.2 (2H, m),7.4-7.5 (2H, m), 8.1-8.3 (2H, m).

IR (KBr): ν 2980, 2909, 1696, 1599 cm⁻¹.

Example 67

Production of Ethyl1-(4-(methbxycarbonyl)benzyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and4-(methoxycarbonyl)benzyl bromide (0.12 g), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (26 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.04 (3H, s), 2.50 (3H, s),3.92 (3H, s), 4.10 (2H, q, J=7.0 Hz), 5.-18 (2H, s), 7.03 (2H, d, J=8.4Hz), 7.42 (2H, d, J=8.8 Hz), 8.02 (2H, d, J=8.4 Hz), 8.22 (2H, d, J=8.8Hz).

IR (KBr): ν 2984, 2951, 1723, 1699 cm⁻¹.

Example 68

Production of Ethyl 2,5-dimethyl-1-(1-naphthylmethyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and1-(chloromethyl)naphthalene (0.10 ml), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (70 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.08 (3H, t, J=6.8 Hz), 2.04 (3H, s), 2.49 (3H, s),4.13 (2H, q, J=6.8 Hz), 5.57 (2H, s), 6.48 (1H, d, J=4.8 Hz), 7.38 (1H,t, J=5.0 Hz), 7.4-7.7 (4H, m), 7.81 (1H, d, J=5.4 Hz), 7.95 (1H, d,J=5.2 Hz), 8.03 (1H, d, J=5.4 Hz), 8.2-8.3 (2H, m).

IR (KBr): ν 3061, 2980, 2942, 1696 cm⁻¹.

Example 69

Production of Ethyl1-(2,4-difluorobenzyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and2,4-difluorobenzyl bromide (0.064 ml), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (109 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.06 (3H, t, J=7.0 Hz), 2.04 (3H, s), 2.50. (3H, s),4.10 (2H, q, J=7.0 Hz), 5.11 (2H, s), 6.4-6.6 (1H, m), 6.8-7.0 (2H, m),7.4-7.5 (2H, m), 8.2-8.3 (2H, m).

IR (KBr): ν 3077, 2982, 2942, 1696 cm⁻¹.

Example 70

Production of Ethyl1-((5-(ethoxycarbonyl)-2-furyl)methyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and ethyl5-(chloromethyl)furan-2-carboxylate(0.080 ml), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (45 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.04 (3H, t, J=6.8 Hz), 1.38 (3H, t, J=6.8 Hz), 2.15(3H, s), 2.60 (3H, s), 4.08 (2H, q, J=6.8 Hz), 4.36 (2H, q, J=6.8 Hz),5.10 (2H, s), 6.11 (1H, d, J=3.6 Hz), 7.10 (1H, d, J=3.6 Hz), 7.38 (2H,d, J=8.4 Hz), 8.21 (2H, d, J=8.4 Hz).

IR (KBr): ν 3123, 2982, 2938, 1726, 1694 cm⁻¹.

Example 71

Production of Methyl4-(3,4-dichlorophenyl)-1-(2,4-difluorobenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (1.0 g) produced in Example 38 and2,4-difluorobenzyl bromide (0.51 ml), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (1.04 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.02 (3H, s), 2.48 (3H, s), 3.63 (3H, s), 5.09 (2H, s),6.46 (1H, q, J=8.4 Hz), 6.8-7.0 (2H, m), 7.09 (1H, dd, J=1.8, 8.2 Hz),7.34 (1H, d, J=1.8 Hz), 7.41 (1H, d, J=8.2 Hz).

IR (KBr): ν 3074, 2948, 2922, 1699 cm⁻¹.

Example 72

Production of Methyl4-(3,4-dichlorophenyl)-2,5-dimethyl-1-(1-phenylethyl)-1H-pyrrole-3-carboxylate

By using the compound (140 mg) produced in Example 38 and 1-phenylethylbromide (0.077 ml), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (49 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 1.91 (3H, d, J=7.6 Hz), 1.91 (3H, s), 2.43 (3H, s),3.59 (3H, s), 5.64 (1H, q, J=7.6 Hz), 7.0-7.2 (3H, m), 7.2-7.4 (5H, m).

IR (KBr): ν 3438, 2986, 2946, 1699 cm⁻¹.

Example 73

Production of Methyl4-(3,4-dichlorophenyl)-2,5-dimethyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

By using the compound (120 mg) produced in Example 38 andbenzenesulfonyl chloride (0.056 ml), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (130 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.27 (3H, s), 2.74 (3H, s), 3.57 (3H, s), 6.98 (1H, dd,J=1.8, 8.0 Hz), 7.23 (1H, d, J=1.8 Hz), 7.41 (1H, d, J=8.0 Hz), 7.4-7.8(5H, m).

IR (KBr): ν 3069, 2949, 1713, 1547 cm⁻¹.

Example 74

Production of Ethyl1-((5-chloro-2-thienyl)methyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (100 mg) produced in Example 1 and2-chloro-5-(chloromethyl)thiophene (0.08 g), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (19 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ 1.04 (3H, t, J=7.0 Hz), 2.12 (3H, s), 2.59 (3H, s),4.08 (2H, q, J=7.0 Hz), 5.13 (2H, s), 6.56 (1H, d, J=3.6 Hz), 6.77 (1H,d, J=3.6 Hz), 7.39 (2H, d, J=8.8 Hz), 8.20 (2H, d, J=8.8 Hz).

IR (KBr): ν 2982, 2941, 1696, 1597 cm⁻¹.

Example 75

Production of Methyl1-benzyl-4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (150 mg) produced in Reference Example 5 and thecompound (130 mg) produced in Reference Example 8, the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (1.38 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.05 (3H, s), 2.51 (3H, s), 3.62 (3H, s), 5.14 (2H, s),6.9-7.0 (2H, m), 7.2-7.4 (3H, m), 7.5-7.6 (1H, m), 7.68 (1H, s), 7.80(1H, d, J=8.0 Hz).

IR (KBr): ν 2980, 2922, 2224, 1699 cm⁻¹.

Example 76

Production of Methyl1-benzyl-4-(3-chloro-4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (150 mg) produced in Reference. Example 5 and4-bromo-2-chlorobenzonitrile (110 mg), the reaction and purificationswere carried out in the same manner as Example 14 to obtain the titledcompound (111 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.04 (3H, s), 2.49 (3H, s), 3.63 (3H, s), 5.12 (2H, s),6.8-7.0 (2H, m), 7.2-7.5 (5H, m), 7.6-7.7 (1H, m).

IR (KBr): ν 2948, 2922, 2228, 1701 cm⁻¹.

Example 77

Production of Methyl1-benzyl-4-(3,4-dicyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (81 mg) produced in Reference Example 5 and thecompound (60 mg) produced in Reference Example 9, the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (37 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.04 (3H, s), 2.51 (3H, s), 3.64 (3H, s), 5.13 (2H, s),6.8-7.0 (2H, m), 7.2-7.4 (3H, m), 7.6-7.8 (3H, m).

IR (KBr): ν 2947, 2232, 1699, 1599 cm⁻¹.

Example 78

Production of Methyl4-(4-cyanophenyl)-1-(4-fluorobenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (1.5 g) produced in Reference Example 7 and4-cyanophenylboronic acid (0.65 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (1.0 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.02 (3H, s), 2.49 (3H, s), 3.61 (3H, s), 5.09 (2H, s),6.8-7.0 (2H, m), 7.0-7.2 (2H, m), 7.35 (2H, d, J=8.2 Hz), 7.64 (2H, d,J=8.2 Hz).

IR (KBr): ν 3048, 2948, 2922, 2226, 1699 cm⁻¹.

Example 79

Production of Methyl1-(4-cyanobenzyl)-4-(3-cyanophenyl)-2,15-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.70 g) produced in Reference Example 17 and3-cyanophenylboronic acid (0.30 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (0.30 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.99 (3H, s), 2.47 (3H, s), 3.61 (3H, s), 5.18 (2H, s),7.05 (2H, d, J=8.4 Hz), 7.4-7.6 (4H, m), 7.66 (2H, d, J=8.4 Hz).

IR (KBr): ν 3067, 2947, 2253, 2228, 1699 cm⁻¹.

Example 80

Production of Methyl1-(4-cyanobenzyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.70 g) produced in Reference Example 17 and4-cyanophenylboronic acid (0.30 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (0.43 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.00 (3H, s), 2.47 (3H, s), 3.61 (3H, s), 5.17 (2H, s),7.05 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz),7.65 (2H, d, J=8.4 Hz).

IR (KBr): ν 2948, 2922, 2253, 2226, 1699 cm⁻¹.

Example 81

Production of Methyl4-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-fluorobenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (479 mg) produced in Reference Example 7 and thecompound (392 mg) produced in Reference Example 8, the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (496 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.04 (3H, s), 2.51 (3H, s), 3.61 (3H, s), 5.10 (2H, s),6.8-7.0 (2H, m), 7.0-7.2 (2H, m), 7.54 (1H, d, J=8.0 Hz), 7.67 (1H, s),7.80 (1H, d, J=8.0 Hz).

Example 82

Production of Methyl4-(4-cyanophenyl)-1-((5-cyano-2-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (180 mg) produced in Example 17 and6-(bromomethyl)nicotinonitrile (0.23 g, produced by a method describedin J. Org. Chem., 65, 7718-7722 (2000)), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (46 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.03 (3H, s), 2.49 (3H, s), 3.61 (3H, s), 5.28 (2H, s),6.79 (1H, d, J=8.0 Hz), 7.35 (2H, d, J=8.4 Hz), 7.65 (2H, d, J=8.4 Hz),7.95 (1H, dd, J=1.8, 8.0 Hz), 8.89 (1H, d, J=1.8 Hz)).

IR (KBr): ν 3059, 2986, 2948, 2226, 1699 cm⁻¹.

Example 83

Production of Methyl4-(4-cyanophenyl)-1-((4-cyano-1,3-thiazol-2-yl)methyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (86 mg) produced in Example 17 and2-(bromomethyl)-1,3-thiazole-4-carbonitrile (0.13 g, produced by amethod described in J. Org. Chem., 65, 7718-7722 (2000)), the reactionand purification were carried out in the same manner as Example 2 toobtain the titled compound (46 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.12 (3H, s), 2.58 (3H, s), 3.61 (3H, s), 5.38 (2H, s),7.33 (2H, d, J=8.0 Hz), 7.65 (2H, d, J=8.0 Hz), 7.99 (1H, s).

IR (KBr): ν 3107, 2948, 2226, 1696 cm⁻¹.

Example 84

Production of Methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carboxylate

By using the compound (0.18 g) produced in Example 17 and3-(chloromethyl)pyridine hydrochloride (0.14 g), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (79 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.04 (3H, s), 2.51 (3H, s), 3.61 (3H, s), 5.15 (2H, s),7.2-7.4 (3H, m), 7.35 (1H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz), 8.3-7(1H, s), 8.56 (1H, d, J=3.2 Hz).

IR (KBr): ν 2988, 2948, 2224, 1699 cm⁻¹.

Example 85

Production of Methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(2-pyridinylmethyl)-1H-pyrrole-3-carboxylate

By using the compound (0.18 g) produced in Example 17 and2-(chloromethyl)pyridine hydrochloride (0.14 g), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (69 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.05 (3H, s), 2.51 (3H, s), 3.61 (3H, s), 5.22 (2H, s),6.63 (1H, d, J=8.4 Hz), 7.1-7.3 (1H, m), 7.36 (2H, d, J=8.0 Hz), 7.64(2H, d, J=8.0 Hz), 7.6-7.8 (1H, m), 8.61 (1H, d, J=4.8 Hz).

IR (KBr): ν 2986, 2922, 2224, 1699 cm⁻¹.

Example 86

Production of4-((3-(4-cyanophenyl)-4-(methoxycarbonyl)-2,5-dimethyl-1H-pyrrole-1-yl)methyl)benzoic Acid

By using the compound (0.18 g) produced in Example 17 and4-bromomethylbenzoic acid (0.18 g), the reaction and purification werecarried out in the same manner as Example 66 to obtain the titledcompound (78 mg) as colorless crystals.

¹H-NMR (DMSO-d₆) δ 2.02 (3H, s), 2.49 (3H, s), 3.62 (3H, s), 5.19 (2H,s), 7.05 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4Hz), 8.09 (2H, d, J=8.4 Hz).

IR (KBr): ν 2498, 2922, 2226, 1699 cm⁻¹.

Example 87

Production of Methyl4-(4-cyanophenyl)-1-(4-methoxybenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (420 mg) produced in Example 17 and4-methoxybenzyl chloride (0.22 ml), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (382 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.03 (3H, s), 2.50 (3H, s), 3.61 (3H, s), 3.80 (3H, s),5.06 (2H, s), 6.87 (4H, s), 7.35 (2H, d, J=8.6 Hz), 7.64 (2H, d, J=8.6Hz).

IR (KBr): ν 3060, 2948, 2837, 2224, 1699 cm⁻¹.

Example 88

Production of Methyl4-(4-cyanophenyl)-1-(4-hydroxybenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylateand4-(4-cyanophenyl)-1-(4-hydroxybenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylicacid

The solution of the compound (370 mg) produced in Example 87 in chloridemethylene (2 ml) was cooled on an ice bath. To the solution was addeddropwise a solution of 1 N boron tribromide in dichloromethane (4 ml).The reaction mixture was stirred at the same temperature for 1 hour,poured into saturated brine and extracted with ethyl acetate. The ethylacetate layer was dried over magnesium sulfate and concentrated. Theresidue was separated by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate) and recrystallized from ethylacetate-hexane to obtain methyl4-(4-cyanophenyl)-1-(4-hydroxybenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate(32 mg) as colorless crystals and4-(4-cyanophenyl)-1-(4-hydroxybenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylicacid (141 mg) and as colorless crystals. Methyl4-(4-cyanophenyl)-1-(4-hydroxybenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

¹H-NMR (CDCl₃) δ 2.03 (3H, s), 2.50 (3H, s), 3.61 (3H, s), 4.98 (1H, s),5.04 (2H, s), 6.81 (4H, s), 7.35 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4Hz).

IR (KBr): ν 2982, 2949, 2228, 1930, 1714 cm⁻¹.4-(4-cyanophenyl)-1-(4-hydroxybenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylicacid

¹H-NMR (DMSO-d₆) δ 2.04 (3H, s), 2.43 (3H, s), 5.07 (2H, s), 6.73 (2H,d, J=8.6 Hz), 6.83 (2H, d, J=8.6 Hz), 7.37 (2H, d, J=8.4 Hz), 7.75 (2H,d, J=8.4 Hz), 9.42 (1H, s).

IR (KBr): ν 3387, 2232, 1661, 1609 cm⁻¹.

Example 89

Production of Methyl1-(2-bromo-4-cyanobenzyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (1.34 g) produced in Example 17 and2-bromo-4-cyanobenzyl bromide (1.45 g, produced by a manner described inJ. Org. Chem., 65, 7718-7722 (2000)), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (990 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.99 (3H, s), 2.44 (3H, s), 3.63 (3H, s), 5.13 (2H, s),6.44 (1H, d, J=8.0 Hz), 7.36 (2H, d, J=8.6 Hz), 7.5-7.6 (1H, m), 7.66(2H, d, J=8.6 Hz), 7.93 (1H, d, J=1.4 Hz).

IR (KBr): ν 2948, 2922, 2226, 1699 cm⁻¹.

Example 90

Production of Methyl4-(4-cyanophenyl)-1-(4-cyano-2-(1-pyrrolidinyl)benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

A mixture of the compound (230 mg) produced in Example 89, pyrrolidine(0.21 ml), sodium tert-butoxide (100 mg),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (15 mg) andtris(dibenzylideneacetone)dipalladium (20 mg) in tetrahydrofuran (2 ml)was stirred for 1 hour under reflux. The reaction mixture was pouredinto saturated brine and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane toobtain the titled compound (107 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.95 (3H, s), 2.0-2.2 (4H, m), 2.42 (3H, s), 3.2-3.4(4H, m), 3.61 (3H, s), 5.05 (2H, s), 6.35 (1H, d, J=8.0 Hz), 7.10 (1H,dd, J=1.4, 8.0 Hz), 7.22 (1H, d, J=1.4 Hz), 7.35 (2H, d, J=8.0 Hz), 7.64(2H, d, J=8.0 Hz).

IR (KBr): ν 2949, 2880, 2226, 1699 cm⁻¹.

Example 91

Production of Methyl1-(4-cyano-2-(4-morpholinyl)benzyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (230 mg) produced in Example 89 and morpholine(0.14 ml), the reaction and purification were carried out in the samemanner as Example 90 to obtain the titled compound (46 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ 1.95 (3H, s), 2.0-2.1 (4H, m), 2.42 (3H, s), 3.2-3.4(4H, m), 5.05 (2H, s), 6.35 (1H, d, J=8.0 Hz), 7.11 (1H, d, J=8.8 Hz),7.2-7.3 (1H, m), 7.35 (2H, d, J=8.0 Hz), 7.64 (2H, d, J=8.0 Hz).

IR (KBr): ν 2953, 2855, 2226, 1699 cm⁻¹.

Example 92

Production of Methyl1-(4-(aminocarbonyl)benzyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

To a solution of the compound (150 mg) produced in Example 86 intetrahydrofuran (1 ml) was added dropwise thionyl chloride (0.08 ml).The reaction mixture was stirred at room temperature for 1 hour, and thesolvent was distilled off under reduced pressure. The residue wasdissolved in tetrahydrofuran(1 ml) and added dropwise to 25% aqueousammonia (2 ml). The reaction mixture was stirred at room temperature for2 hours, poured into saturated brine and extracted with ethyl acetate.The ethyl acetate layer was dried over magnesium sulfate andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to obtain the titled compound (71 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 2.02 (3H, s), 2.49 (3H, s), 3.62 (3H, s), 5.17 (2H,brs), 5.75 (1H, brs), 6.01 (1H, brs), 7.03 (2H, d, J=8.4 Hz), 7.36 (2H,d, J=8.8 Hz), 7.64 (2H, d, J=8.4 Hz), 7.80 (2H, d, J=8.8 Hz).

IR (KBr): ν 3355, 3183, 2949, 2226, 1682 cm⁻¹.

Example 93

Production of Methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(4-((methylamino)carbonyl)benzyl)-1H-pyrrole-3-carboxylate

By using the compound (150 mg) produced in Example 86 and an aqueoussolution of methylamine (2 ml), the reaction and purification werecarried out in the same manner as Example 92 to obtain the titledcompound (46 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.01 (3H, s), 2.48 (3H, s), 3.02 (3H, d, J=5.2 Hz),3.61 (3H, s), 5.16 (2H, s), 6.13 (1H, s), 7.00 (2H, d, J=8.4 Hz), 7.29(2H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz).

IR (KBr): ν 3329, 2948, 2226, 1699, 1653 cm⁻¹.

Example 94

Production of Methyl4-(4-cyanophenyl)-1-(4-((dimethylamino)carbonyl)benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

A solution of the compound (120 mg) produce Example 86, 2N dimethylaminetetrahydrofuran solution (0.5 ml), 1-hydroxybenzotriazole monohydrate(52 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(65 mg) in N,N-dimethylformamide (6 ml) was stirred at room temperaturefor 6 hours. The reaction mixture was poured into saturated brine andextracted with ethyl acetate. The ethyl acetate layer was dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) andrecrystallized from ethyl acetate-hexane to obtain the titled compound(58 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.02 (3H, s), 2.49 (3H, s), 2.98 (3H, s), 3.11 (3H, s),3.61 (3H, s), 5.14 (2H, s), 6.97 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.4Hz), 7.41 (2H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz).

IR (KBr): ν 2948, 2224, 1699, 1634 cm⁻¹.

Example 95

Production of Methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylate

By using the compound (0.20 g) produced in Example 17 andmethanesulfonyl chloride (0.074 ml), the reaction and purification werecarried out in the same manner as Example 66 to obtain the titledcompound (191 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.27 (3H, s), 2.79 (3H, s), 3.25 (3H, s), 3.57 (3H, s),7.28 (2H, d, J=8.0 Hz), 7.67 (2H, d, J=8.0 Hz).

IR (KBr): ν 3009, 2934, 2228, 1929, 1713 cm⁻¹.

Example 96

Production of Methyl4-(4-cyanophenyl)-1-(ethylsulfonyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.20 g) produced in Example 17 and ethanesulfonylchloride (0.095 ml), the reaction and purification were carried out inthe same manner as Example 66 to obtain the titled compound (99 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 1.40 (3H, t, J=7.2 Hz), 2.26 (3H, s), 2.78 (3H, s),3.35 (2H, q, J=7.2 Hz), 3.57 (3H, s), 7.28 (2H, d, J=7.8 Hz), 7.66 (2H,d, J=7.8 Hz).

IR (KBr): ν 2982, 2949, 2228, 1930, 1714 cm⁻¹.

Example 97

Production of Methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(propylsulfonyl)-1H-pyrrole-3-carboxylate

By using the compound (0.20 g) produced in Example 17 and1-propanesulfonyl chloride (0.11 ml), the reaction and purification werecarried out in the same manner as Example 66 to obtain the titledcompound (170 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.09 (3H, t, J=7.0 Hz), 1.86 (2H, sextet, J=7.0 Hz),2.26 (3H, s), 2.77 (3H, s), 3.2-3.4 (2H, m), 3.57 (3H, s), 7.38 (2H, d,J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz).

IR (KBr): ν 2972, 2938, 2228, 1713 cm⁻¹.

Example 98

Production of Methyl4-(4-cyanophenyl)-1-(isopropylsulfonyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.20 g) produced in Example 17 andisopropylsulfonyl chloride (0.05 ml), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (195 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.41 (6H, d, J=7.0 Hz), 2.25 (3H, s), 2.77 (3H, s),3.46 (1H, septet; J=7.0 Hz), 3.57 (3H, s), 7.28 (2H, d, J=8.4 Hz), 7.66(2H, d, J=8.4 Hz).

IR (KBt): ν 2986, 2949, 2228, 1929, 1713 cm⁻¹.

Example 99

Production of Methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(4-pyridinylmethyl)-1H-pyrrole-3-carboxylate

By using the compound (0.49 g) produced in Example 17 and4-(chloromethyl)pyridine hydrochloride (0.41 g), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (403 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.02 (3H, s), 2.48 (3H, s), 3.62 (3H, s), 5.13 (2H, s),6.88 (2H, d, J=5.8 Hz), 7.36 (2H, d, J=8.2 Hz), 7.65 (2H, d, J=8.2 Hz),8.59 (2H, d, J=5.8 Hz).

IR (KBr): ν 2947, 2224, 1699, 1603 cm⁻¹.

Example 100

Production of Methyl4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (630 mg) produced in Reference Example 11 and thecompound (530 mg) produced in Reference Example 8, the reaction andpurification were carried out in the same manner as Example 14 to obtainthe titled compound (393 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.16 (3H, s), 2.53 (3H, s), 3.64 (3H, s), 7.55 (1H, d,J=8.0 Hz), 7.67 (1H, s), 7.80 (1H, d, J=8.0 Hz), 8.15 (1H, s).

IR (KBr): ν 3320, 2951, 2230, 1674 cm⁻¹.

Example 101

Production of Methyl4-(4-cyano-3-(trifluoromethyl)phenyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate

By using the compound (78 mg) produced in Example 100 and methyl iodide(0.031 ml), the reaction and purification were carried out in the samemanner as Example 2 to obtain the titled compound (62 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 2.12 (3H, s), 2.56 (3H, s), 3.49 (3H, s), 3.59 (3H, s),7.50 (1H, d, J=8.4 Hz), 7.63 (1H, s), 7.79 (1H, d, J=8.4 Hz).

IR (KBr): ν 2249, 2230, 1699, 1178 cm⁻¹.

Example 102

Production of Methyl1-(4-cyanobenzyl)-4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (120 mg) produced in Example 100 and 4-cyanobenzylbromide (63 mg), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (116 mg) asyellow crystals.

¹H-NMR (CDCl₃) δ 2.03 (3H, s), 2.48 (3H, s), 3.62 (3H, s), 5.19 (2H, s),7.05 (2H, d, J=8.1 Hz), 7.54 (1H, d, J=7.5 Hz), 7.6-7.7 (3H, m), 7.80(1H, d, J=8.1 Hz).

IR (KBr): ν 2990, 2949, 2230, 1699 cm⁻¹.

Example 103

Production of 4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylicAcid

By using the compound (1.01 g) produced in Example 17, the reaction andpurification were carried out in the same manner as Example 88 to obtainthe titled compound (0.68 g) as yellow crystals.

¹H-NMR (DMSO-d₆) δ 2.05 (3H, s), 2.39 (3H, s), 7.35 (2H, d, J=8.4 Hz),7.71 (2H, d, J=8.4 Hz).

IR (KBr): ν 3565, 3215, 2253, 1651 cm⁻¹.

Example 104

Production of 4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxamide

By using the compound (500 mg) produced in Example 103, the reaction andpurification were carried out in the same manner as Example 92 to obtainthe titled compound (265 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.15 (3H, s), 2.52 (3H, s), 4.99 (1H, brs), 5.25 (1H,brs), 7.43 (2H, d, J=8.0 Hz), 7.68 (2H, d, J=8.0 Hz), 8.27 (1H, s).

IR (KBr): ν 3320, 2951, 2230, 1674 cm⁻¹.

Example 105

Production of 4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

To a solution of the compound (250 mg) produced in Example 104 andpyridine (0.13 ml) in N,N-dimethylformamide (5 ml) was added dropwiseoxalyl chloride (0.11 ml) under ice cooling, and the mixture was stirredat the same temperature for 0.5 hour. The reaction mixture was pouredinto saturated brine and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane toobtain the titled compound (190 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.32 (3H, s), 2.44 (3H, s), 7.52 (2H, d, J=8.4 Hz),7.70 (2H, d, J=8.4 Hz), 8.26 (1H, s).

IR (KBr): ν 3272, 3185, 2216, 1606 cm⁻¹.

Example 106

Production of1-(4-cyanobenzyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (80 mg) produced in Example 105 and 4-cyanobenzylbromide (63 mg), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (89 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 2.18 (3H, s), 2.36 (3H, s), 5.17 (2H, s), 7.04 (2H, d,J=8.1 Hz), 7.52 (2H, d, J=8.4 Hz), 7.67 (2H, d, J=8.4 Hz), 7.71 (2H, d,J=8.1 Hz).

IR (KBr): v 3058, 2951, 2920, 2216 cm⁻¹.

Example 107

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (80 mg) produced in Example 105 and3-(chloromethyl)pyridine hydrochloride (71 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (61 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.21 (3H, s), 2.39 (3H, s), 5.14 (2H, s), 7.18 (1H, d,J=7.8 Hz), 7.3-7.4 (1H, m), 7.51 (2H, d, J=8.4 Hz), 7.71 (2H, d, J=8.4Hz), 8.36 (1H, s), 8.59 (1H, s).

IR (KBr): ν 3038, 2953, 2922, 2216 cm⁻¹.

Example 108

Production of Methyl4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carboxylate

By using the compound (120 mg) produced in Example 100 and3-(chloromethyl)pyridine hydrochloride (71 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (55 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.06 (3H, s), 2.52 (3H, s), 3.61 (3H, s), 5.16 (2H, s),7.1-7.3 (2H, m), 7.53 (1H, d, J=8.4 Hz), 7.66 (1H, s), 7.80 (1H, d,J=8.4 Hz), 8.35 (1H, s), 8.56 (1H, s).

IR (KBr): ν 2948, 2224, 1699, 1634 cm⁻¹.

Example 109

Production of Methyl1-((6-chloro-3-pyridinyl)methyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (1.08 g) produced in Example 17 and2-chloro-5-(chloromethyl)pyridine (0.13 g), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (767 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.03 (3H, s), 2.50 (3H, s), 3.60 (3H, s), 5.12 (2H, s),7.14 (1H, dd, J=8.4, 2.4 Hz), 7.2-7.4 (3H, m), 7.63 (2H, d, J=8.4 Hz),8.12 (1H, d, J=2.4 Hz).

IR (KBr): ν 2988, 2947, 2224, 1696 cm⁻¹.

Example 110

Production of Methyl4-(4-cyanophenyl)-1-((6-fluoro-3-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (550 mg) produced in Example 17 and5-(chloromethyl)-2-fluoropyridine (0.13 g, produce by a method describedin J. Org. Chem., 65, 7718-7722 (2000)), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (398 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.04 (3H, s) 2.51 (3H, s), 3.61 (3H, s), 5.13 (2H, s),6.93 (1H, dd, J=2.7, 7.5 Hz), 7.2-7.4 (1H, m), 7.33 (2H, d, J=7.5 Hz),7.63 (2H, d, J=7.5 Hz), 7.93 (1H, s).

IR (KBr): ν 2990, 2949, 2224, 1699 cm⁻¹.

Example 111

Production of Methyl4-(4-cyanophenyl)-1-((6-methoxy-3-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

A solution of the compound (160 mg) produced in Example 110 and sodiummethoxide (34 mg) in N,N-dimethylformamide (3 ml) was stirred at 120° C.for 24 hours under reflux. The reaction mixture was poured intosaturated brine and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane toobtain the titled compound (21 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.05 (3H, s), 2.52 (3H, s), 3.60 (3H, s), 3.92 (3H, s),5.05 (2H, s), 6.73 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=2.6, 8.8 Hz), 7.33(2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz), 7.79 (1H, d, J=2.6 Hz).

IR (KBr): ν 2988, 2947, 2226, 1699 cm⁻¹.

Example 112

Production of Methyl1-(4-cyano-2-fluorobenzyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (600 mg) produced in Example 17 and4-cyano-2-fluorobenzyl bromide (510 mg, produce by a method described inJ. Org. Chem., 65, 7718-7722 (2000)), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (156 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.01 (3H, s), 2.47 (3H, s), 3.62 (3H, s), 5.20 (2H, s),6.5-6.7 (1H, m), 7.35 (2H, d, J=8.6 Hz), 7.4-7.5 (2H, m), 7.65 (2H, d,J=8.6 Hz).

IR (KBr): ν 3069, 2949, 2226, 1699 cm⁻¹.

Example 113

Production of Methyl4-(4-cyanophenyl)-2,5-dimethyl-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)-1H-pyrrole-3-carboxylate

By using the compound (550 mg) produced in Example 17 and5-(chloromethyl)-2-(trifluoromethyl)pyridine (0.46 g), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (399 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.03 (3H, s), 2.50 (3H, s), 3.61 (3H, s), 5.23 (2H, s),7.2-7.4 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.4-7.6 (1H, m), 7.64 (2H, d,J=8.4 Hz), 8.47 (1H, s).

IR (KBr): ν 2990, 2949, 2226, 1699 cm⁻¹.

Example 114

Production of Methyl4-(4-cyanophenyl)-1-((2-cyano-4-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (600 mg) produced in Example 17 and4-(chloromethyl)pyridine-2-carbonitrile (330 mg, produced by a methoddescribed in J. Org. Chem., 65, 7718-7722 (2000)), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (134 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.01 (3H, s), 2.47 (3H, s), 3.63 (3H, s), 5.18 (2H, s),7.08 (1H, d, J=4.4 Hz), 7.28 (1H, d, J=5.0 Hz), 7.36 (2H, d, J=8.4 Hz),7.66 (2H, d, J=8.4 Hz), 8.71 (1H, d, J=5.0 Hz).

IR (KBr): ν 3058, 2988, 2224, 1693 cm⁻¹.

Example 115

Production of1-((6-chloro-3-pyridinyl)methyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (150 mg) produced in Example 105 and6-chloro-3-(chloromethyl)pyridine (130 mg), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (133 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.01 (3H, s), 2.40 (3H, s), 5.13 (2H, s), 7.16 (1H, dd,J=2.2, 8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.51 (2H, d, J=8.4 Hz), 7.72(2H, d, J=8.4 Hz), 8.13 (1H, d, J=2.2 Hz).

IR (KBr): ν 3051, 2986, 2314, 1607 cm⁻¹.

Example 116

Production of Methyl4-(3,4-dichlorophenyl)-2,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carboxylate

By using the compound (200 mg) produced in Example 38 and3-(chloromethyl)pyridine hydrochloride (130 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (103 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.00 (3H, s), 2.46 (3H, s), 3.63 (3H, s), 5.16 (2H, s),7.0-7.2 (2H, m), 7.2-7.4 (2H, m), 7.41 (1H, d, J=8.2 Hz), 8.37 (1H, m),8.55 (1H, d, J=4.4 Hz).

IR (KBr): ν 2990, 2948, 1699, 1533 cm⁻¹.

Example 117

Production of Methyl1-((6-chloro-3-pyridinyl)methyl)-4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (150 mg) produced in Example 100 and2-chloro-5-(chloromethyl)pyridine (90 mg), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (91 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.05 (3H, s), 2.52 (3H, s), 3.61 (3H, s), 5.14 (2H, s),7.16 (1H, dd, J=2.4, 8.6 Hz), 7.34 (1H, d, J=8.4 Hz), 7.52 (1H, d, J=8.8Hz), 7.66 (1H, s), 7.81 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=2.4 Hz).

IR (KBr): ν 2996, 2949, 2230, 1699 cm⁻¹.

Example 118

Production of Methyl4-(4-cyanophenyl)-1-((2-cyano-3-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (450 mg) produced in Example 17 and3-(bromomethyl)pyridine-2-carbonitrile (500 mg, produced by a methoddescribed in J. Org. Chem., 65, 7718-7722 (2000)), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (61 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.02 (3H, s), 2.48 (3H, s), 3.61 (3H, s), 5.35 (2H, s),6.93 (1H, d, J=8.1 Hz), 7.34 (2H, d, J=8.7 Hz), 7.49 (4H, dd, J=4.8, 6.8Hz), 7.64 (2H, d, J=8.7 Hz), 8.66 (1H, d, J=4.8 Hz).

IR (KBr): ν 3054, 2992, 2949, 2253, 2226 cm⁻¹.

Example 119

Production of3-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2-pyridinecarbonitrile

By using the compound (180 mg) produced in Example 105 and3-(bromomethyl)pyridine-2-carbonitrile (500 mg, produced by a methoddescribed in J. Org. Chem., 65, 7718-7722 (2000)), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (91 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 2.38 (3H, s), 5.35 (2H, s), 6.94 (1H, d,J=8.0 Hz), 7.52 (2H, d, J=8.0 Hz), 7.2-7.4 (1H, m), 7.73 (2H, d, J=8.0Hz), 8.71 (1H, d, J=4.4 Hz).

IR (KBr): ν 3069, 2949, 2226, 1699 cm⁻¹.

Example 120

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-(2-pyrazinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (230 mg) produced in Example 105 and2-(bromomethyl)pyrazine (200 mg, produced by a method described in J.Org. Chem., 65, 7718-7722 (2000)), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (198 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.26 (3H, s), 2.45 (3H, s), 5.23 (2H, s), 7.52 (2H, d,J=8.8 Hz,), 7.71 (2H, d, J=8.8 Hz), 8.26 (1H., s), 8.58 (2H, s).

IR (KBr): v 3048, 2988, 2951, 2215, 1607 cm⁻¹.

Example 121

Production of5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)nicotinonitrile

By using the compound (540 mg) produced in Example 105 and5-(chloromethyl)nicotinonitrile (600 mg, produced by a method describedin J. Org. Chem., 65, 7718-7722 (2000)), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (99 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.21 (3H, s), 2.39 (3H, s), 5.20 (2H, s), 7.46 (1H, s),7.52 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 8.52 (1H, d, J=2.1 Hz),8.86 (1H, s).

IR (KBr): ν 3057, 2990, 2216, 1609 cm⁻¹.

Example 122

Production of 4-(4-cyanophenyl)-3,5-dimethyl-1H-pyrrole-2-carbonitrile

By using the compound (1.99 g) produced in Reference Example 12 and4-cyanophenylboronic acid (1.62 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (1.09 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 2.29 (3H, s), 7.34 (2H, d, J=8.4 Hz),7.70 (2H, d, J=8.4 Hz), 8.71 (1H, s).

IR (KBr): ν 3277, 3071, 2215, 1674, 1609 cm⁻¹.

Example 123

Production of4-(4-cyanophenyl)-3,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-2-carbonitrile

By using the compound (620 mg) produced in Example 122 and3-(chloromethyl)pyridine hydrochloride (550 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (467 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.18 (3H, s), 2.21 (3H, s), 5.24 (2H, s), 7.2-7.4 (3H,m), 7.4-7.5 (1H, m), 7.6-7.8 (2H, m), 8.42 (1H, s), 8.59 (1H, d, J=4.6Hz).

IR (KBr): ν 3026, 2990, 2226, 2207, 1607 cm⁻¹.

Example 124

Production of Methyl4-(4-cyanophenyl)-2-ethyl-5-methyl-1H-pyrrole-3-carboxylate

By using the compound (6.01 g) produced in Reference Example 1 andmethyl 3-oxopentanoate (12 ml), the reaction and purification werecarried out in the same manner as Example 1 to obtain the titledcompound (5.8 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.28 (3H, t, J=7.2 Hz), 2.14 (3H, s), 2.97 (2H, q,J=7.2 Hz), 3.62 (3H, s), 7.35 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz),8.07 (1H, s).

IR (KBr): ν 3318, 2975, 2949, 2226, 1682 cm⁻¹.

Example 125

Production of 4-(4-cyanophenyl)-2-ethyl-5-methyl-1H-pyrrole-3-carboxylicAcid

By using the compound (86 mg) produced in Example 124, the reaction andpurification were carried out in the same manner as Example 88 to obtainthe titled compound (46 mg) as colorless crystals.

¹H-NMR (DMSO-d₆) δ 1.11 (3H, t, J=7.4 Hz), 2.00 (3H, s), 2.79 (2H, q,J=7.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.67 (2H, d, J=8.4 Hz), 11.11 (1H,s), 11.36 (1H, s).

IR (KBr): ν 3300, 2982, 2226, 1651 cm⁻¹.

Example 126

Production of4-(4-cyanophenyl)-2-ethyl-5-methyl-1H-pyrrole-3-carboxamide

By using the compound (1.29 g) produced in Example 125, the reaction andpurification were carried out in the same manner as Example 92 to obtainthe titled compound (1.09 g) as colorless crystals.

¹H-NMR (DMSO-d₆) δ 1.16 (3H, t, J=7.2 Hz), 2.15 (3H, s), 2.70 (2H, q,J=7.2 Hz), 6.48 (1H, brs), 6.80 (1H, brs), 7.37 (2H, d, J=8.4 Hz), 7.73(2H, d, J=8.4 Hz), 10.88 (1H, s).

IR (KBr): ν 3321, 2974, 2224, 1653 cm ⁻¹.

Example 127

Production of4-(4-cyanophenyl)-2-ethyl-5-methyl-1H-pyrrole-3-carbonitrile

By using the compound (950 mg) produced in Example 126, the reaction andpurification were carried out in the same manner as Example 105 toobtain the titled compound (694 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.33 (3H, t, J=7.5 Hz), 2.32 (3H, s), 2.81 (2H, q,J=7.5 Hz), 7.52 (2H, d, J=8.7 Hz), 7.69 (2H, d, J=8.4 Hz), 8.35 (1H, s).

IR (KBr): ν 3277, 3046, 2976, 2215, 1607 cm⁻¹.

Example 128

Production of4-(4-cyanophenyl)-2-ethyl-5-methyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (580 mg) produced in Example 127 and3-(chloromethyl)pyridine hydrochloride (530 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (421 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.23 (3H, t, J=7.8 Hz), 2.18 (3H, s), 2.79 (2H, q,J=7.8 Hz), 5.17 (2H, s), 7.1-7.2 (1H, m), 7.2-7.4 (1H, m), 7.52 (2H, d,J=8.8 Hz), 7.71 (2H, d, J=8.8 Hz), 8.35 (1H, d, J=1.8 Hz), 8.58 (1H, d,J=4.4 Hz).

IR (KBr): ν 3034, 2976, 2938, 2215, 1607 cm⁻¹.

Example 129

Production of Methyl4-(4-cyanophenyl)-2-isopropyl-5-methyl-1H-pyrrole-3-carboxylate

By using the compound (6.00 g) produced in Reference Example 1 andmethyl 4-methyl-3-oxopentanoate (13.8 ml), the reaction and purificationwere carried out in the same manner as Example 1 to obtain the titledcompound (5.09 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.30 (6H, d, J=6.6 Hz), 2.14 (3H, s), 3.60 (3H, s),3.79 (1H, septet, J=6.6 Hz), 7.34 (2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0Hz), 8.13 (1H, s).

IR (KBr): ν 3320, 2970, 2870, 2226, 1682 cm⁻¹.

Example 130

Production of4-(4-cyanophenyl)-2-isopropyl-5-methyl-1H-pyrrole-3-carboxylic Acid

By using the compound (4.2 g) produced in Example 129, the reaction andpurification were carried out in the same manner as Example 88 to obtainthe titled compound (1.41 g) as colorless crystals.

¹H-NMR (DMSO-d₆) δ 1.16 (6H, d, J=7.2 Hz), 2.02 (3H, s), 3.69 (1H,septet, J=6.6 Hz), 7.30 (2H, d, J=8.0 Hz), 7.66 (2H, d, J=8.0 Hz), 10.96(1H, s), 11.37 (1H, s).

IR (KBr): ν 3337, 2967, 2226, 1661 cm⁻¹.

Example 131

Production of4-(4-cyanophenyl)-2-isopropyl-5-methyl-1H-pyrrole-3-carboxamide

By using the compound (1.34 g) produced in Example 130, the reaction andpurification were carried out in the same manner as Example 92 to obtainthe titled compound (0.53 g) as colorless crystals.

¹H-NMR (DMSO-d₆) δ 1.21 (6H, d, J=7.0 Hz), 2.17 (3H, s), 3.35 (1H,septet, J=7.0 Hz), 6.50 (1H, brs), 6.83 (1H, brs), 7.38 (2H, d, J=8.0Hz), 7.73 (2H, d, J=8.0 Hz), 10.76 (1H, s).

IR (KBr): ν 3345, 2962, 2224, 1609 cm⁻¹.

Example 132

Production of4-(4-cyanophenyl)-2-isopropyl-5-methyl-1H-pyrrole-3-carbonitrile

By using the compound (950 mg) produced in Example 131, the reaction andpurification were carried out in the same manner as Example 105 toobtain the titled compound (358 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.37 (6H, d, J=7.0 Hz), 2.32 (3H, s), 3.24 (1H, septet,J=7.0 Hz), 7.53 (2H, d, J=8.0 Hz), 7.70 (2H, d, J=8.0 Hz), 8.24 (1H, s).

IR (KBr): ν 3289, 2971, 2213, 1609 cm⁻¹.

Example 133

Production of4-(4-cyanophenyl)-2-isopropyl-5-methyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (320 mg) produced in Example 132 and3-(chloromethyl)pyridine hydrochloride (250 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (132 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.39 (6H, d, J=7.0 Hz), 2.18 (3H, s)3, 3.02 (1H,septet, J=7.0 Hz), 5.18 (2H, s), 7.1-7.2 (1H, m), 7.2-7.4 (1H, m), 7.52(2H, d, J=8.6 Hz), 7.72 (2H, d, J=8.6 Hz), 8.34 (1H, s), 8.58 (2H, d,J=4.8 Hz).

IR (KBr): ν 2973, 2932, 2215, 1607 cm⁻¹.

Example 134

Production of Methyl4-(4-cyanophenyl)-2,5-diethyl-1H-pyrrole-3-carboxylate

By using the compound (3.54 g) produced in Reference Example 14 andmethyl 3-oxopentanoate (6 ml), the reaction and purification werecarried out in the same manner as Example 1 to obtain the titledcompound (3.7 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.10 (3H, t, J=7.4 Hz), 1.29 (3H, t, J=7.4 Hz), 2.49(2H, q, J=7.4 Hz), 2.98 (2H, q, J=7.4 Hz), 3.61 (3H, s), 7.34 (2H, d,J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz), 8.08 (1H, s).

IR (KBr): ν 3326, 2973, 2878, 2226, 1747, 1682 cm⁻¹.

Example 135

Production of 4-(4-cyanophenyl)-2,5-diethyl-1H-pyrrole-3-carboxylic Acid

By using the compound (2.87 g) produced in Example 134, the reaction andpurification were carried out in the same manner as Example 88 to obtainthe titled compound (1.91 g) as colorless crystals.

¹H-NMR (DMSO-d₆) δ 1.0-1.2 (6H, m), 2.2-2.4 (2H, m), 2.7-2.9 (2H, m),7.2-7.4 (2H, m), 7.6-7.8 (2H, m), 11.08 (1H, s), 11.18 (1H, s).

IR (KBr): ν 3310, 2973, 2936, 2230, 1699 cm⁻¹.

Example 136

Production of 4-(4-cyanophenyl)-2,5-diethyl-1H-pyrrole-3-carboxamide

By using the compound (1.80 g) produced in Example 135, the reaction andpurification were carried out in the same manner as Example 92 to obtainthe titled compound (0.78 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.15 (3H, t, J=7.6 Hz), 1.29 (3H, t, J=7.6 Hz), 2.50(2H, q, J=7.6 Hz), 3.01 (2H, q, J=7.4 Hz), 5.07 (2H, brs), 7.44 (2H, d,J=8.4 Hz), 7.68 (2H, d, J=8.4 Hz), 8.24 (1H, s).

IR (KBr): ν 3337, 2973, 2226, 1680, 1643 cm⁻¹.

Example 137

Production of 4-(4-cyanophenyl)-2,5-diethyl-1H-pyrrole-3-carbonitrile

By using the compound (700 mg) produced in Example 136, the reaction andpurification were carried out in the same manner as Example 105 toobtain the titled compound (366 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.24 (3H, t, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz), 2.68(2H, q, J=7.6 Hz), 2.82 (2H, q, J=7.6 Hz), 7.51 (2H, d, J=8.4 Hz), 7.69(2H, d, J=8.4 Hz), 8.32 (1H, s).

IR (KBr): ν 3326, 2973, 2878, 2226, 1747, 1682 cm⁻¹.

Example 138

Production of4-(4-cyanophenyl)-2,5-diethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (320 mg) produced in Example 137 and3-(chloromethyl)pyridine hydrochloride (250 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (132 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.11 (3H, t, J=7.6 Hz), 1.21 (3H, t, J=7.6 Hz), 2.55(2H, q, J=7.6 Hz), 2.72 (2H, q, J=7.6 Hz), 5.19 (2H, s), 7.13 (1H, d,J=7.8 Hz), 7.2-7.4 (1H, m), 7.53 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4Hz), 8.33 (1H, d, J=1.4 Hz), 8.5-8.6 (1H, m).

IR (KBr): ν 3040, 2973, 2940, 2215 cm⁻¹.

Example 139

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-(4-pyrimidinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (620 mg) produced in Example 105 and4-(chloromethyl)pyrimidine (540 mg, Produced by a method described in J.Org. Chem., 65, 7718-7722 (2000)), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (19 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.21 (3H, s), 2.40 (3H, s), 5.17 (2H, s), 6.76 (1H, d,J=5.0 Hz), 7.53 (2H, d, J=8.6 Hz), 7.72 (2H, d, J=8.6 Hz), 8.75 (1H, d,J=5.0 Hz), 9.22 (1H, s).

IR (KBr): ν 3042, 2972, 2222, 1582 cm⁻¹.

Example 140

Production of4-(4-cyanophenyl)-1-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (600 mg) produced in Example 105 and2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (780 mg), the reactionand purification were carried out in the same manner as Example 2 toobtain the titled compound (665 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.16 (3H, s), 2.24 (3H, s), 2.29 (3H, s), 2.34 (3H, s),3.79 (3H, s), 5.07 (2H, s), 7.53 (2H, d, J=8.0 Hz), 7.68 (2H, d, J=8.0Hz), 8.16 (1H, s).

IR (KBr): ν 2947, 2926, 2224, 2213, 1608 cm⁻¹.

Example 141

Production of4-(4-cyanophenyl)-1-((4-hydroxy-3,5-dimethyl-2-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (180 mg) produced in Example 140, the reaction andpurification were carried out in the same manner as Example 88 to obtainthe titled compound (104 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.00 (3H, s), 2.14 (3H, s), 2.16 (3H, s), 2.37 (3H, s),5.08 (2H, s), 7.3-7.5 (3H, m), 7.67 (2H, d, J=8.1 Hz).

IR (KBr): ν 2955, 2890, 2215, 1633 cm⁻¹.

Example 142

Production of5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2,4-dimethyl-3-pyridinylBenzenesulfonate

By using the compound (120 mg) produced in Example 105 andbenzenesulfonic acid 5-(bromomethyl)-2,4-dimethyl-3-pyridinyl (200 mg,produced by a method described in J. Org. Chem., 65, 7718-7722 (2000)and J. Org. Chem., 61, 813-815 (1996)), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (131 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.18 (6H, s), 2.33 (3H, s), 2.37 (3H, s), 5.03 (2H, s),7.33 (1H, s), 7.51 (2H, d, J=8.0 Hz), 7.6-7.8 (5H, m), 8.00 (2H, d,J=8.0 Hz).

IR (KBr): ν 3072, 2921, 2216, 1609 cm⁻¹.

Example 143

Production of4-(4-cyanophenyl)-1-((5-hydroxy-4,6-dimethyl-3-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

A solution of the compound (95 mg) produced in Example 142 and anhydrouspotassium carbonate (100 mg) in methanol (3 ml) was stirred for 10minutes under reflux. The reaction mixture was poured into saturatedbrine and extracted with ethyl acetate. The ethyl acetate layer wasdried over magnesium sulfate and concentrated. The residue was purifiedby column chromatography (carrier: silicagel eluant: hexane-ethylacetate) and recrystallized from ethyl acetate-hexane to obtain thetitled compound (58 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.17 (3H, s), 2.29 (3H, s), 2.34 (3H, s), 2.48 (3H, s),5.02 (2H, s), 7.03 (1H, s), 7.51 (2H, d, J=8.4 Hz), 7.71 (2H, d, J=8.4Hz).

IR (KBr): ν 2928, 2867, 2215, 1609 cm⁻¹.

Example 144

Production of4-(4-cyanophenyl)-1-((5-hydroxy-2-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (140 mg) produced in Example 105 and6-(bromomethyl)-3-pyridinyl benzenesulfonate (201 mg, produced by amethod described in J. Org. Chem., 65, 7718-7722 (2000) and J. Org.Chem., 61, 813-815 (1996)), the reaction and purification were carriedout in the same manner as Example 2 to obtain the titled compound (51mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.23 (3H, s), 2.40 (3H, s), 5.13 (2H, s), 5.95 (1H,brs), 6.66 (1H, d, J=8.4 Hz), 7.16 (1H, dd, J=3.0, 8.8 Hz), 7.51 (2H, d,J=8.4 Hz), 7.70 (2H, d, J=8.4 Hz), 8.24 (1H, d, J=3.0 Hz).

IR (KBr): ν 3339, 2982, 2215, 1607 cm⁻¹.

Example 145

Production of Methyl5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)nicotinate

By using the compound (600 mg) produced in Example 105 and methyl5-(chloromethyl)nicotinate (750 mg, produced by a method described in J.Org. Chem., 65, 7718-7722 (2000)), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (205 mg) as colorless crystals.

¹H-NMR (CDCl₃) 6 2.22 (3H, s), 2.40 (3H, s), 3.97 (3H, s), 5.19 (2H, s),7.52 (2H, d, J=8.0 Hz), 7.72 (2H, d, J=8.0 Hz), 7.89 (1H, s), 8.44 (1H,d, J=2.2 Hz), 9.18 (1H, d, J=1.4 Hz).

IR (KBr): ν 3042, 2972, 2222, 1582 cm⁻¹.

Example 146

Production of4-(4-cyanophenyl)-1-((5-(1-hydroxy-1-methylethyl)-3-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

To a solution of the compound (80 mg) produced in Example 145 intetrahydrofuran (2 ml) was added dropwise a 3N solution ofmethylmagnesium bromide in tetrahydrofuran (0.37 ml) under ice cooling.The reaction mixture was stirred at the same temperature for 1 hour. Thereaction mixture was poured into saturated brine and extracted withethyl acetate. The ethyl acetate layer was dried over magnesium sulfateand concentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to obtain the titled compound (64 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 1.60 (6H, s), 2.22 (3H, s), 2.40 (3H, s), 5.14 (2H, s),7.4-7.6 (1H, m), 7.52 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 8.08(1H, s), 8.65 (1H, s).

IR (KBr): ν 3042, 2972, 2222, 1582 cm⁻¹.

Example 147

Production of Ethyl4-(4-cyanophenyl)-5-methyl-2-phenyl-1H-pyrrole-3-carboxylate

By using the compound (4.96 g) produced in Reference Example 1 and ethyl3-oxo-3-phenylpropanoate (15.2 g), the reaction and purification werecarried out in the same manner as Example 1 to obtain the titledcompound (155 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 0.93 (3H, t, J=7.4 Hz), 2.22 (3H, s), 4.00 (2H, q,J=7.4 Hz), 7.3-7.5 (5H, m), 7.54 (2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.4Hz), 8.24 (1H, s).

IR (KBr): ν 3203, 2982, 2226, 1682 cm⁻¹.

Example 148

Production of4-(4-cyanophenyl)-1-((4,5-dimethoxy-3-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (300 mg) produced in Example 105 and3-(chloromethyl)-4,5-dimethoxypyridine (430 mg), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (224 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.24 (3H, s), 2.43 (3H, s), 3.79 (3H, s), 3.94 (3H, s),5.18 (2H, s), 6.83 (1H, d, J=5.4 Hz), 7.51. (2H, d, J=8.4 Hz), 7.68 (2H,d, J=8.4 Hz), 8.19 (1H, d, J=5.4 Hz).

IR (KBr): ν 2982, 2948, 2213, 1607 cm⁻¹.

Example 149

Production of Ethyl4-(4-cyanophenyl)-5-methyl-2-phenyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carboxylate

By using the compound (120 mg) produced in Example 147 and3-(chloromethyl)pyridine hydrochloride (94 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (152 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.26 (3H, t, J=6.8 Hz), 2.04 (3H, s)., 4.12 (2H, q,J=6.8 Hz), 5.00 (2H, s), 7.1-7.4 (7H, m), 7.48 (2H, d, J=8.4 Hz), 7.66(2H, d, J=8.4 Hz), 8.21 (1H, s), 8.51 (1H, d, J=5.0 Hz).

IR (KBr): ν 3203, 2982, 2226, 1682 cm⁻¹.

Example 150

Production of4-(4-cyanophenyl)-1-((6-fluoro-3-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (600 mg) produced in Example 105 and5-(chloromethyl)-2-fluoropyridine (400 mg, produced by a methoddescribed in J. Org. Chem., 65, 7718-7722 (2000)), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (432 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.22 (3H, s), 2.40 (3H, s), 5.13 (2H, s), 6.97 (1H, dd,J=3.0, 8.4 Hz), 7.2-7.4 (1H, m), 7.51 (2H, d, J=8.4 Hz), 7.72 (2H, d,J=8.4 Hz), 7.94 (1H, s).

IR (KBr): ν 3056, 2922, 2216, 1607 cm⁻¹.

Example 151

Production of Benzenesulfonic Acid5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2-pyridinyl

By using the compound (400 mg) produced in Example 105 and5-(bromomethyl)-2-pyridinyl benzenesulfonate (830 mg, produced by amethod described in J. Org. Chem., 61, 813-815 (1996)), the reaction andpurification were carried out in the same manner as Example 2 to obtainthe titled compound (498 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.17 (3H, s), 2.33 (3H, s), 5.11 (2H, s), 6.64 (1H, s),6.78 (1H, d, J=5.1 Hz), 7.4-7.6 (4H, m), 7.6-7.8 (3H, m), 8.01 (2H, d,J=7.2 Hz), 8.25 (1H, d, J=5.1 Hz).

IR (KBr): ν 3065, 2988, 2216, 1607 cm⁻¹.

Example 152

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((6-oxo-1,6-dihydro-3-pyridinyl)methyl)-1H-pyrrole-3-carbonitrile

By using the compound (310 mg) produced in Example 151, the reaction andpurification were carried out in the same manner as Example 143 toobtain the titled compound (158 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 2.37 (3H, s), 4.94 (2H, s), 5.8-6.0 (1H,m), 6.0-6.1 (1H, m), 7.3-7.4 (1H, m), 7.51 (2H, d, J=8.4 Hz), 7.72 (2H,d, J=8.4 Hz).

IR (KBr): ν 3078, 2951, 2840, 2216, 1661, 1609 cm⁻¹.

Example 153

Production of4-(4-cyanophenyl)-2-ethyl-1-((5-hydroxy-2-pyridinyl)methyl)-5-methyl-1H-pyrrole-3-carbonitrile

By using the compound (70 mg) produced in Example 127 and6-(bromomethyl)-3-pyridinyl benzenesulfonate (120 mg, produced by amethod described in J. Org. Chem., 61, 813-815 (1996)), the reaction wascarried out in the same manner as Example 2, whereby an alkylationreaction and a de-benzensulphonylation reaction proceededsimultaneously. Purification was carried out in the same manner asExample 2 to obtain the titled compound (47 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.20 (3H, t, J=7.4 Hz), 2.19 (3H, s), 2.79 (2H, q,J=7.4 Hz), 5.16 (2H, s), 6.62 (1H, d, J=8.4 Hz), 6.69 (1H, s), 7.17 (1H,dd, J=3.0, 8.4 Hz), 7.51 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.4 Hz), 8.24(1H, d, J=2.6 Hz).

IR (KBr): ν 3380, 2980, 2215, 1607 cm⁻¹.

Example 154

Production of4-(4-cyanophenyl)-1-((5-hydroxy-2-pyridinyl)methyl)-2-isopropyl-5-methyl-1H-pyrrole-3-carbonitrile

By using the compound (180 mg) produced in Example 132 and6-(bromomethyl)-3-pyridinyl benzenesulfonate (260 mg, produced by amethod described in J. Org. Chem., 61, 813-815 (1996)), the reaction wascarried out in the same manner as Example 2, whereby an alkylationreaction and a de-benzensulphonylation reaction proceededsimultaneously. Purification was carried out in the same manner asExample 2 to obtain the titled compound (130 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.37 (6H, d, J=7.0 Hz), 2.20 (3H, s), 3.08 (1H, septet,J=7.0 Hz), 5.17 (2H, s), 5.97 (1H, s), 6.60 (1H, d, J=8.4 Hz), 7.16 (1H,dd, J=3.0, 8.4 Hz), 7.52 (2H, d, J=8.4 Hz), 7.71 (2H, d, J=8.4 Hz), 8.24(1H, d, J=2.6 Hz).

IR (KBr): ν 3429, 2976, 2213, 1607 cm⁻¹.

Example 155

Production of 4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (400 mg) produced in Reference Example 13 and3-cyanophenylboronic acid (0.31 g), the reaction and purification werecarried out in the same manner as Example 14 to obtain the titledcompound (213 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.29 (3H, s), 2.44 (3H, s), 7.4-7.8 (4H, m), 8.24 (1H,s).

IR (KBr): ν 3287, 2928, 2215, 1593 cm⁻¹.

Example 156

Production of4-(3-cyanophenyl)-2,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (80 mg) produced in Example 155 and3-(chloromethyl)pyridine hydrochloride (140 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (76 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 52.19 (3H, s), 2.39 (3H, s), 5.15 (2H, s), 7.1-7.4 (2H,m), 7.4-7.8 (4H, m), 8.37 (1H, s), 8.59 (1H, d, J=3.8 Hz).

IR (KBr): ν 3034, 2922, 2215, 1603 cm⁻¹.

Example 157

Production of1-((6-chloro-3-pyridinyl)methyl)-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (80 mg) produced in Example 155 and2-chloro-5-(chloromethyl)pyridine (90 mg), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (23 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.19 (3H, s), 2.39 (3H, s), 5.12 (2H, s), 7.15 (1H, dd,J=2.6, 8.4 Hz), 7.35 (1H, d, J=8.0 Hz), 7.5-7.8 (4H, m), 8.14 (1H, d,J=2.6 Hz).

IR (KBr): ν 3053, 2919, 2215, 1462 cm⁻¹.

Example 158

Production of4-(4-formyl-1-naphthyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (410 mg) produced in Reference Example 13 and4-formyl-1-naphthylboronic acid (450 mg), the reaction and purificationwere carried out in the same manner as Example 14 to obtain the titledcompound (285 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.06 (3H, s), 2.50 (3H, s), 7.5-7.7 (2H, m), 7.6-7.8(1H, m), 7.88 (1H, d, J=7.8 Hz), 8.03 (1H, d, J=7.8 Hz), 8.31 (1H, s),9.34 (1H, d, J=8.4 Hz), 10.42 (1H, s).

IR (KBr): ν 3264, 2921, 2214, 1682, 1574 cm⁻¹.

Example 159

Production of4-(4-cyano-1-naphthyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

A solution of the compound (241 mg) obtained Example 158, hydroxylaminehydrochloride (73 mg) in 1-methylpyrrolidine-2-one (1.5 ml) was heatedat 110° C. for 2 hours with stirring. The reaction mixture was pouredinto saturated brine and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane toobtain the titled compound (188 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.05 (3H, s), 2.48 (3H, 5), 7.4-8.0 (5H, m), 8.30 (1H,d, J=8.0 Hz), 8.37 (1H, s).

IR (KBr): ν 3287, 3056, 2921, 2218, 1580 cm⁻¹.

Example 160

Production of4-(4-7cyano-1-naphthyl)-2,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (140 mg) produced in Example 159 and3-(chloromethyl)pyridine hydrochloride (180 mg), the reaction andpurification were carried out in the same manner as Example 66 to obtainthe titled compound (97 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.98 (3H, s), 2.44 (3H, s), 5.20 (2H, s), 7.2-7.3 (1H,m), 7.3-7.4 (1H, m), 7.48 (1H, d J=7.2 Hz), 7.60 (1H, t, J=7.2 Hz), 7.71(1H, t, J=7.2 Hz), 7.82 (1H, d, J=8.4 Hz), 7.96 (1H, d, J=7.5 Hz) 8.31(1H, d, J=8.1 Hz), 8.39 (1H, d, J=1.5 Hz), 8.61 (1H, dd, J=1.5, 3.0 Hz).

IR (KBr): ν 3036, 2951, 2922, 2218, 1578 cm⁻¹.

Example 161

Production of Methyl1-(4-cyanobenzyl)-4-(3,4-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (200 mg) produced in Example 38 and 4-cyanobenzylbromide (120 mg), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (95 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 2.00 (3H, s), 2.46 (3H, s), 3.63 (3H, s), 5.16 (2H, s),7.0-7.2 (3H, m), 7.33 (1H, d, J=1.8 Hz), 7.41 (1H, d, J=8.4 Hz), 7.65(2H, d, J=8.4 Hz).

IR (KBr): ν 2990, 2948, 2230, 1699 cm⁻¹.

Example 162

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((6-methyl-3-pyridinyl)methyl)-1H-pyrrole-3-carbonitrile

A solution of the compound (420 mg) produced in Example 105 the compound(470 mg) produced in Reference Example 18 and(tributylphosphoranylidene)acetonitrile (920 mg) in toluene (10 ml) wasstirred for 20 hours under reflux. The reaction mixture was poured intosaturated brine and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane toobtain the titled compound (266 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.21 (3H, s), 2.39 (3H, s), 2.56 (3H, s), 5.10 (2H, s),7.07 (1H, dd, J=2.6, 8.0 Hz), 7.16 (1H, d, J=8.0 Hz), 7.51 (2H, d, J=8.4Hz), 7.71 (2H, d, J=8.4 Hz), 8.23 (1H, d, J=2.6 Hz).

IR (KBr): ν 3052, 2922, 2215, 1607 cm⁻¹.

Example 163

Production of Methyl5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2-pyridinecarboxylate

By using the compound (1.62 g) produced in Example 105 and methyl5-(bromomethyl)pyridine-2-carboxylate (1.68 g, produced from thecompound of Reference Example 15 by a method described in J. Org. Chem.,65, 7718-7722 (2000)), the reaction and purification were carried out inthe same manner as Example 2 to obtain the titled compound (721 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 2.39 (3H, s), 4.02 (3H, s), 5.22 (2H, s),7.29 (1H, dd, J=2.1, 7.8 Hz), 7.50 (2H, d, J=7.8 Hz), 7.71 (2H, d, J=7.8Hz), 8.13 (1H, d, J=7.8 Hz), 7.49 (2H, d, J=1.5 Hz).

IR (KBr): ν 3054, 2951, 2216, 1726, 1609 cm⁻¹.

Example 164

Production of 4-(4-cyanophenyl)-1-((6-(1-hydroxy-1-methylethyl)-3-pyridinyl)methyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (130 mg) produced in Example 163, the reaction andpurification were carried out in the same manner as Example 146 toobtain the titled compound (54 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 1.54 (6H, s), 2.22 (3H, s), 2.40 (3H, s), 4.52 (1H, s),5.14 (2H, s), 7.22 (1H, dd, J=1.8, 8.4 Hz), 7.40 (1H, d, J=8.4 Hz), 7.51(2H, d, J=8.1 Hz), 7.71 (2H, d, J=8.1 Hz), 8.21 (1H, d, J=8.1 Hz).

IR (KBr): ν 3364, 2975, 2924, 2216, 1607 cm⁻¹.

Example 165

Production of Tert-butyl5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2-pyridinylcarbamate

By using the compound (350 mg) produced in Example 105 and tert-butyl5-(bromomethyl)pyridin-2-ylcarbamate (820 mg, produced from the compoundof Reference Example 16 by a method described in J. Org. Chem., 65,7718-7722 (2000)), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (223 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 1.52 (9H, s), 2.21 (3H, s), 2.40 (3H, s), 5.05 (2H, s),7.2-7.3 (1H, m), 7.50 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.4 Hz), 7.89(1H, d, J=1.8 Hz), 7.94 (1H, d, J=8.7 Hz).

IR (KBr): ν 3171, 2980, 2216, 1728, 1607 cm⁻¹.

Example 166

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((1-oxide-3-pyridinyl)methyl)-1H-pyrrole-3-carbonitrile

A mixture of the compound (103 mg) produced in Example 107,m-chloroperbenzoic acid (140 mg) and dichloromethane (3 ml) was stirredat room temperature for 14 hours. The reaction mixture was poured intosaturated brine and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate and concentrated. The residue waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane toobtain the titled compound (30 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.22 (3H, s), 2.40 (3H, s), 5.09 (2H, s), 6.86 (1H, d,J=7.8 Hz), 7.2-7.4 (1H, m), 7.51 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4Hz), 7.84 (1H, s), 8.17 (1H, d, J=5.7 Hz).

IR (KBr): ν 3040, 2953, 2216, 1609, 1541 cm⁻¹.

Example 167

Production of5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2-pyridineCarboxylic Acid

A solution of the compound (544 mg) produced in Example 163 and 1Nsodium hydroxide solution (3 ml) in ethanol (3 ml) was stirred at roomtemperature for 2 hours. The reaction mixture was poured into saturatedbrine, neutralized with hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was dried over magnesium sulfate andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to obtain the titled compound (467 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ 2.22 (3H, s), 2.40 (3H, s), 5.26 (2H, s), 7.4-7.6 (3H,m), 7.73 (2H, d, J=8.1 Hz), 8.26 (1H, d, J=8.1 Hz), 8.33 (1H, s).

IR (KBr): ν 3400, 3067, 2924, 2222, 1728, 1609 cm⁻¹.

Example 168

Production of1-((6-amino-3-pyridinyl)methyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

A solution of the compound (192 mg) produced in Example 165 intrifluoroacetic acid (1 ml ) was stirred at room temperature for 0.5hour and concentrated. The residue was poured into saturated brine,neutralized with aqueous solution of sodium hydrogencarbonate andextracted with ethyl acetate. The ethyl acetate layer was dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) andrecrystallized from ethyl acetate-hexane to obtain the titled compound(125 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.23 (3H, s), 2.41 (3H, s), 4.51 (2H, brs), 4.98 (2H,s), 6.49 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.4Hz), 7.80 (1H, s).

IR (KBr): ν 3366, 2922, 2214, 1609, 1505 cm⁻¹.

Example 169

Production of5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2-pyridineCarboxamide

By using the compound (107 mg) produced in Example 167 and a 25% aqueoussolution of ammonia (2 ml), the reaction and purification were carriedout in the same manner as Example 92 to obtain the titled compound (114mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.21 (3H, s), 2.40 (3H, s), 5.21 (2H, s), 5.59 (1H,brs), 7.42 (1H, d, J=8.4 Hz), 7.52 (2H, d, J=8.0Hz), 7.6-7.8 (3H, m),8.2-8.3 (2H, m).

IR (KBr): ν 3166, 2953, 2216, 1682, 1609 cm⁻¹.

Example 170

Production of5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-N-methyl-2-pyridineCarboxamide

By using the compound (107 mg) produced in Example 167 and an aqueoussolution of methylamine (2 ml), the reaction and purification werecarried out in the same manner as Example 92 to obtain the titledcompound (68 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.21 (3H, s), 2.40 (3H, s), 3.04 (3H, d, J=5.2 Hz),5.20 (2H, s), 7.41 (1H, d, J=8.4 Hz), 7.52 (2H, d, J=8.8 Hz), 7.72 (2H,d, J=8.8 Hz), 7.94 (1H, s), 8.2-8.3 (2H, m).

IR (KBr): ν 3389, 3050, 2953, 2216, 1674 cm⁻¹.

Example 171

Production of5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-N,N-dimethyl-2-pyridineCarboxamide

By using the compound (107 mg) produced in Example 167 and an aqueoussolution of dimethylamine (2 ml,), the reaction and purification werecarried out in the same manner as Example 92 to obtain the titledcompound (69 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.21 (3H, s), 2.40 (3H, s), 3.11 (3H, s), 3.15 (3H, s),5.18 (2H, s), 7.2-7.4 (1H, m), 7.52 (2H, d, J=8.6 Hz), 7.6-7.8 (3H, m),8.29 (1H, d, J=1.6 Hz).

IR (KBr): ν 2930, 2216, 1634, 1609, 1541 cm⁻¹.

Example 172

Production ofN-(5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2-pyridinyl)acetamide

To a mixture of the compound (81 mg) produced in Example 168,triethylamine(0.083 ml) and tetrahydrofuran (1 ml) was added acetylchloride (0.021 ml) at room temperature. The reaction mixture wasstirred at room temperature for 0.5 hour. The residue was poured intosaturated brine, neutralized with aqueous solution of sodium bicarbonateand extracted with ethyl acetate. The ethyl acetate layer was dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) andrecrystallized from ethyl acetate-hexane to obtain the titled compound(57 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.22 (6H, s), 2.40 (3H, s), 5.09 (2H, s), 7.2-7.4 (1H,m), 7.51 (2H, d, J=8.4 Hz), 7.71 (2H, d, J=8.4 Hz), 7.91 (1H, d, J=2.0Hz), 7.99 (1H, s), 8.21 (1H, d, J=8.4 Hz).

IR (KBr): ν 3327, 3100, 2986, 2214, 1689 cm⁻¹.

Example 173

Production of5-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-2-pyridineCarbonitrile

By using the compound (81 mg) produced in Example 169, the reaction andpurification were carried out in the same manner as Example 105 toobtain the titled compound (54 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 2.38 (3H, s), 5.22 (2H, s), 7.29 (1H, dd,J=2.1, 8.1 Hz), 7.50 (2H, d, J=8.7 Hz), 7.6-7.8 (3H, m), 8.47 (1H, d,J=2.1 Hz).

IR (KBr): ν 3065, 2988, 2216, 1609 cm⁻¹.

Example 174

Production of1-((6-bromo-3-pyridinyl)methyl)-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (2.11 g) produced in Example 105 and2-bromo-5-(bromomethyl)pyridine (2.38 g, produced by a method describedin J. Org. Chem., 61, 813-815 (1996)), the reaction and purificationwere carried out in the same manner as Example 2 to obtain the titledcompound (2.54 g) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 2.39 (3H, s); 5.09 (2H, s), 7.04 (1H, dd,J=2.7, 8.4 Hz), 7.4-7.6 (3H, m), 7.71 (2H, d, J=8.1 Hz), 8.10 (1H, d,J=2.7 Hz).

IR (KBr): ν 3053, 2949, 2920, 2215, 1609 cm⁻¹.

Example 175

Production of4-{[3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl]methyl}benzoicAcid

By using the compound (880 mg) produced in Example 105 and4-(bromomethyl)benzoic acid (920 mg), the reaction and purification werecarried out in the same manner as Example 2 to obtain the titledcompound (720 mg) as colorless crystals.

¹H-NMR (DMSO-d6) δ 2.15 (3H, s), 2.31 (3H, s), 5.34 (2H, s), 7.10 (2H,d, J=7.8 Hz), 7.56 (2H, d, J=7.8 Hz), 7.8-8.0 (4H, m).

Example 176

Production of4-((3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)methyl)-N,N-dimethylbenzamide

By using the compound (100 mg) produced in Example 175 and 50% aqueoussolution of dimethylamine (2 ml), the reaction and purification werecarried out in the same manner as Example 92 to obtain the titledcompound (43 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 2.38 (3H, s), 2.98 (3H, s), 3.11 (3H, s),5.14 (2H, s), 6.96 (2H, d, J=8.0 Hz), 7.43 (2H, d, J=8.0 Hz), 7.53 (2H,d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz).

IR (KBr): ν 2932, 2214, 1633, 1608, 1398 cm⁻¹.

Example 177

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-(4-(1-pyrrolidinylcarbonyl)benzyl)-1H-pyrrole-3-carbonitrile

By using the compound (100 mg) produced in Example 175 and pyrrolidine(0.3 ml), the reaction and purification were carried out in the samemanner as Example 92 to obtain the titled compound (34 mg) as colorlesscrystals.

¹H-NMR -(CDCl₃) δ 1.8-2.1 (4H, m), 2.19 (3H, s), 2.38 (3H, s), 3.3-3.5(2H, m), 3.6-3.8 (2H, m), 5.13 (2H, s), 6.96 (2H, d, J=8.6 Hz), 7.53(4H, d, J=8.4 Hz), 7.71 (2H, d, J=8.6 Hz).

IR (KBr): ν 2978, 2926, 2880, 2224, 1607, 1427 cm⁻¹.

Example 178

Production of Methyl4-(1,1′-biphenyl-4-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.23 g) produced in Reference Example 2 and1,1′-biphenyl-4-ylboronic acid (0.20 g), the reaction and purificationwere carried out in the same manner as Example 14 to obtain the titledcompound (186 mg) as pale yellow crystals.

¹H-NMR (CDCl₃) δ 2.16 (3H, s), 2.52 (3H, s), 3.64 (3H, s), 7.2-7.4 (3H,m), 7.4-7.5 (2H, m), 7.5-7.7 (4H, m), 8.04 (1H, s).

IR (KBr): ν 3303, 3027, 2948, 1682 cm⁻¹.

Example 179

Production of Tert-butyl2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (8.00 g) produced in Reference Example 1 andtert-butyl acetoacetate (14.7 ml), the reaction and purification werecarried out in the same manner as Example 1 to obtain the titledcompound (1.26 g) as yellow crystals.

IR (KBr): ν 3285, 1659, 1514, 1343, 1159, 1101, 854 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.32 (9H, s), 2.13 (3H, s), 2.51 (3H, s), 7.39 (2H, d,J=8.7 Hz), 7.99 (1H, br), 8.21 (2H, d, J=8.7 Hz).

Example 180

Production of Tert-butyl1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (0.19 g) produced in Example 179 and benzylbromide (0.09 ml), the reaction and purification were carried out in thesame manner as Example 2 to obtain the titled compound (0.16 g) asyellow crystals.

IR (KBr): ν 2976, 1694, 1597, 1514, 1343, 1152, 855, 731 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.28 (9H, s), 2.03 (3H, s), 2.49 (3H, s), 5.11 (2H,s), 6.95-6.98. (2H, m), 7.26-7.44 (5H, m), 8.20-8.24 (2H, m).

Example 181

Production of 2,5-dimethyl-3-(4-nitrophenyl)-1H-pyrrole

The compound (0.80 g) produced in Example 179 was dissolved in TFA (7ml), and the solution was stirred at room temperature for 7 hours andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) to obtain the titledcompound (0.49 g) as a pale brown powder.

IR (KBr): ν 3358, 1593, 1499, 1323, 1113,. 853, 775, 758 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.27 (3H, s), 2.43 (3H, s), 6.07-6.08 (1H, m),7.46-7.53 (2H, m), 7.87 (1H, br), 8.16-8.23 (2H, m).

Example 182

Production of 1-benzyl-2,5-dimethyl-3-(4-nitrophenyl)-1H-pyrrole and3-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole

By using the compound (0.39 g) produced in Example 181 and benzylbromide (0.26 ml), the reaction and purification were carried out in thesame manner as Example 2 to obtain1-benzyl-2,5-dimethyl-3-(4-nitrophenyl)-1H-pyrrole (0.10 g) as yellowcrystals and 3-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole (0.01 g)as yellow crystals. 1-benzyl-2,5-dimethyl-3-(4-nitrophenyl)-1H-pyrrole

IR (KBr): ν 1593, 1507, 1343, 1327 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 2.31 (3H, s), 5.09 (2H, s), 6.17 (1H,s), 6.94 (2H, d, J=7.2 Hz), 7.24-7.36 (3H, m), 7.49-7.54 (2H, m),8.19-8.23 (2H, m).

3-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole

IR (KBr): ν 3407, 1593, 1507, 1345, 856 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.18 (3H, s), 2.28 (3H, s), 3.79 (2H, s), 7.03-7.27(7H, m), 7.77 (1H, br), 8.10-8.15 (2H, m).

Example 183

Production of Methyl2,5-dimethyl-4-(4-nitrophenyl)-1-phenyl-1H-pyrrole-3-carboxylate

A mixture of the compound (0.40 g) produced in Reference Example 1,methyl acetoacetate (0.43ml), aniline (0.20ml) and methanol (7 ml) wasstirred at room temperature for 18 hours and at 70° C. for 5 hours andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) to obtain the titledcompound (0.05 g) as yellow crystals.

¹H-NMR (CDCl₃) δ: 1.90 (3H, s), 2.32 (3H, s), 3.65 (3H, s), 7.23-7.26(2H, m), 7.43-7.58 (5H, m), 8.23 (2H, d, J=8.7 Hz).

Example 184

Production of Methyl1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (4.64 g) produced in Reference Example 1, methylacetoacetate (5.18 g), benzyl amine (2.63 g) and methanol (75 ml), thereaction and purification were carried out in the same manner as Example183 to obtain the titled compound (1.40 g) as yellow crystals.

IR (KBr): ν 1699, 1514, 1341 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 2.51 (3H, s), 3.62 (3H, s), 5.13 (2H,s), 6.94-6.96 (2H, m), 7.29-7.43 (5H, m), 8.22 (2H, d, J=8.7 Hz).

Example 185

Production of1-(1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrol-3-yl)ethanone

A mixture of the compound (0.42 g) obtained in Reference Example1,2,4-pentandione (0.41 ml), benzylamine (0.24 ml) and dimethylformamide(10 ml) was stirred at room temperature for 18 hours and at 80° C. for24 hours, poured into water and extracted with ethyl acetate. The ethylacetate layer was washed with water and saturated brine, successively,dried over magnesium sulfate and concentrated. The residue was purifiedby column chromatography (carrier: silicagel, eluant: hexane-ethylacetate) to obtain the titled compound (0.12 g) as yellow crystals.

IR (KBr): ν 1651, 1597, 1516, 1348 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.98 (3H, s), 2.04 (3H, s), 2.46 (3H, s), 5.13 (2H,s), 6.97 (2H, d, J=7.2 Hz), 7.30-7.45 (5H, m), 8.26 (2H, d, J=9.0 Hz).

Example 186

Production of1-(1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrol-3-yl)ethanol

The compound (0.14 g) produced in Example 185 was dissolved in methanol(3 ml) and tetrahydrofuran (1 ml) and to the solution was added sodiumboron hydride (0.28 g). The reaction mixture was stirred at roomtemperature for 16 hours and concentrated. The residue was diluted withwater and extracted with ethyl acetate. The ethyl acetate layer wasdried over magnesium sulfate and concentrated. The residue was purifiedby column chromatography (carrier: silicagel, eluant: hexane-ethylacetate) and recrystallized from ethyl acetate-hexane to obtain thetitled compound (0.02 g) as pale brown solids.

IR (KBr): ν 1595, 1514, 1345, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.42 (3H, d, J=7.0 Hz), 2.09 (3H, s), 2.30 (3H, s),4.96 (1H, q, J=7.0 Hz), 5.08 (2H, s), 6.95 (2H, d, J=7.4 Hz), 7.26-7.53(5H, m), 8.23 (2H, d, J=8.8 Hz).

Example 187

Production ofN,1-dibenzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide

To a solution of the compound (45 mg) produced in Example 47, benzylamine (0.028 ml) and triethylamine (0.028 ml) in dimethylformamide (0.5ml) was added cyanide diethylphosphate (0.024 ml) and the reactionmixture was stirred at room temperature for 4 hours. The reactionmixture was poured into water and extracted with ethyl acetate. Theethyl acetate layer was washed with 1N hydrochloric acid, water andsaturated sodium bicarbonate water, successively, dried over magnesiumsulfate, and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) toobtain the titled compound (31 mg) as yellow crystals.

¹H-NMR (CDCl₃) δ: 2.07 (3H, s), 2.48 (3H, s), 4.38 (2H, d, J=5.7 Hz),5.11 (2H, s), 5.18 (1H, brm), 6.96 (2H, d, J=6.6 Hz), 7.02-7.05 (2H, m),7.24-7.37 (8H, m), 8.05 (2H, d, J=9.0 Hz).

Example 188

Production of1-benzyl-N,2,5-trimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide

By using the compound (105 mg) produced in Example 47 as a startingmaterial and a 2M solution of methylamine in tetrahydrofuran (0.5 ml) asan amine component, the reaction and purification were carried out inthe same manner as Example 187 to obtain the titled compound (9 mg) asyellow crystals.

IR (KBr): ν 1595, 1508, 1339 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.45 (3H, s), 2.75 (3H, d, J=5.1 Hz),4.99 (1H, br), 5.11 (2H, s), 6.96 (2H, d, J=6.6 Hz), 7.26-7.48 (5H, m),8.26 (2H, d, J=9.0 Hz).

Example 189

Production of1-benzyl-N,N,2,5-tetramethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide

By using the compound (105 mg) produced in Example 47 as a startingmaterial and a 2M solution of dimethylamine in tetrahydrofuran (0.5 ml)as an amine component, the reaction and purification were carried out inthe same manner as Example 187 to obtain the titled compound (71 mg) asyellow crystals.

IR (KBr): ν 1620, 1595, 1510, 1339 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.22 (6H, s), 2.61 (3H, s), 2.95 (3H, s), 5.09 (2H,s), 6.97 (2H, d, J=6.6 Hz), 7.25-7.42 (5H, m), 8.19 (2H, d, J=9.0 Hz).

Example 190

Production of1-benzyl-N-(2-(4-hydroxyphenyl)ethyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide

By using the compound (105 mg) produced in Example 47 as a startingmaterial and 2-(4-hydroxyphenyl)ethylamine (82 mg) as an aminecomponent, the reaction and purification were carried out in the samemanner as Example 187 to obtain the titled compound (69 mg) as yellowcrystals.

IR (KBr): ν 1595, 1514, 1339 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.04 (3H, s), 2.43 (3H, s), 2.58 (2H, t, J=6.6 Hz),3.49 (2H, q, J=6.6 Hz), 4.97-5.01 (2H, m), 5.08 (2H, s), 6.63 (2H, d,J=8.4 Hz), 6.78 (2H, d, J=8.4 Hz), 6.94 (2H, d, J=7.2 Hz), 7.26-7.35(5H, m), 8.10 (2H, d, J=9.0 Hz).

Example 191

Production of1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide

By using the compound (105 mg) produced in Example 47, ammonium chloride(54 mg), triethylamine (0.21 ml) and cyanide diethylphosphate (0.055ml), the reaction and purification were carried out in the same manneras Example 187 to obtain the titled compound (36 mg) as yellow crystals.

IR (KBr): ν 1653, 1595, 1508, 1339 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.08 (3H, s), 2.49 (3H, s), 4.85-5.25 (2H, br), 5.12(2H, s), 6.96 (2H, d, J=6.9 Hz), 7.27-7.37 (3H, m), 7.50 (2H, d, J=8.7Hz), 8.25 (2H, d, J=8.7 Hz).

Example 192

Production of1-benzyl-N-butyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide

By using the compound (105 mg) produced in Example 47 as a startingmaterial and n-butylamine (0.060 ml) as an amine component, the reactionand purification were carried out in the same manner as Example 187 toobtain the titled compound (55 mg) as yellow crystals.

IR (KBr): ν 1638, 1595, 1508, 1339 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.81 (3H, t, J=6.6Hz), 1.09 (2H, sextet, J=6.6 Hz),1.27 (2H, quint, J=6.6 Hz), 2.10 (3H, s), 2.45 (3H, s), 3.21 (2H, q,J=6.6 Hz), 5.00 (1H, brm), 5.11 (2H, s), 6.97 (2H, d, J=6.6. Hz),7.26-7.50 (5H, m), 8.25 (2H, d, J=9.0 Hz).

Example 193

Production of1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-N-undecyl-1H-pyrrole-3-carboxamide

By using the compound (105 mg) produced in Example 47 as a startingmaterial and n-undecyl amine (0.13 ml) as an amine component, thereaction and purification were carried out in the same manner as Example187 to obtain the titled compound (83 mg) as yellow crystals.

IR (KBr): ν 1638, 1595, 1514, 1339 cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=6.6 Hz), 1.04-1.32 (18H, m), 2.10 (3H,s), 2.45 (3H, s), 3.20 (2H, q, J=6.6 Hz), 5.00 (1H, brm), 5.11 (2H, s),6.97 (2H, d, J=6.6 Hz), 7.26-7.50 (5H, m), 8.25 (2H, d, J=9.0 Hz).

Example 194

Production of Tert-butyl6-(((1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrol-3-yl)carbonyl)amino)hexylcarbamate

By using the compound (105 mg) produced in Example 47 as a startingmaterial and tert-butyl N-(6-aminohexyl)carbamate (130 mg) as an aminecomponent, the reaction and purification were carried out in the samemanner as Example 187 to obtain the titled compound (77 mg) as yellowcrystals.

IR (KBr): ν 1696, 1638, 1595, 1514, 1339 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.04-1.43 (8H, m), 1.44 (9H, s), 2.10 (3H, s), 2.45(3H, s), 3.05 (2H, q, J=6.6 Hz), 3.20 (2H, q, J=6.6 Hz), 4.55 (1H, br),5.03 (1H, br), 5.11 (2H, s), 6.97 (2H, d, J=7.2 Hz), 7.25-7.50 (5H, m),8.25 (2H, d, J=9.0 Hz).

Example 195

Production of4-((1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrol-3-yl)carbonyl)morpholine

By using the compound (105 mg) produced in Example 47 as a startingmaterial and morpholine (0.052 ml) as an amine component, the reaction,and purification were carried out in the same manner as Example 187 toobtain the titled compound (59 mg) as yellow crystals.

IR (KBr): ν 1622, 1595, 1512, 1339, 1113, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 2.24 (3H, s), 2.60-2.80 (8H, brm), 5.09(2H, s), 6.93 (2H, d, J=6.6 Hz), 7.25-7.43 (5H, m), 8.22 (2H, d, J=9.0Hz).

Example 196

Production of1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-N-(2-(1-piperidinyl)ethyl)-1H-pyrrole-3-carboxamide

To a solution of the compound (105 mg) produced in Example 47,1-(2-aminoethyl)piperidine (0.086 ml) and triethylamine (0.063 ml) indimethylformamide (1 ml) was added cyanide diethylphosphate (0.055 ml)and the reaction mixture was stirred at room temperature for 16 hours.The reaction mixture was poured into saturated sodium bicarbonate waterand extracted with ethyl acetate. The ethyl acetate layer was dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: Chromatorex NH-silica gel, produced by FujiSilysia Chemical Lyd., eluant: hexane-ethyl acetate) to obtain thetitled compound (67 mg) as yellow crystals.

IR (KBr): ν 1638,. 1595, 1541, 1512, 1339 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.26-1.29 (6H, br), 2.04-2.07, (4H, br), 2.11 (3H, s),2.19 (3H, t, J=6.0 Hz), 2.46 (3H, s), 3.31 (2H, q, J=6.0 Hz), 5.11 (2H,s), 5.74 (1H, brm), 6.99 (2H, d, J=7.2 Hz), 7.26-7.50 (5H, m), 8.24 (2H,d, J=9.0 Hz).

Example 197

Production of Tert-butyl1-(2,4-difluorobenzyl)-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

By using the compound (4.16 g) produced in Reference Example 1,tert-butyl acetoacetate (6.33 g) and 2,4-difluorobenzyl amine (3.15 g),the reaction and purification were carried out in the same manner asExample 185 to obtain the titled compound (1.33 g) as yellow crystals.

IR (KBr): ν 1694, 1514, 1436, 1152 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.28 (9H, s), 2.02 (3H, s), 2.48 (3H, s), 5.09 (2H,s), 6.46-6.58 (1H, m), 6.78-6.93 (2H, m), 7.40 (2H, d, J=9.0 Hz), 8.22(2H, d, J=9.0 Hz).

Example 198

Production of1-(2,4-difluorobenzyl)-2,5-dimethyl-3-(4-nitrophenyl)-1H-pyrrole

By using the compound (0.44 g) produced in Example 197, the reaction andpurification were carried out in the same manner as Example 181 toobtain the titled compound (0.24 g) as yellow crystals.

IR (KBr): ν 1593, 1507, 1341 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.30 (3H, s), 5.08 (2H, s), 6.17 (1H,s), 6.39-6.50 (1H, m), 6.75-6.92 (2H, m), 7.48-7.54 (2H, m), 8.18-8.25(2H, m).

Example 199

Production of Tert-butyl4-(3,4-dichlorophenyl)-1-(2,4-difluorobenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (1.16 g) produced in Reference Example 19,tert-butyl acetoacetate (1.66 ml) and 2,4-difluorobenzyl amine (0.65ml), the reaction and purification were carried out in the same manneras Example 185 to obtain the titled compound (0.16 g) as colorlesscrystals.

IR (KBr): ν 1690, 1155 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 2.00 (3H, s), 2.46 (3H, s), 5.07 (2H,s), 6.45-6.56 (1H, m), 6.77-6.92 (2H, m), 7.07 (1H, dd, J=8.2, 2.0 Hz),7.34 (1H, d, J=2.0 Hz), 7.41 (1H, d, J=8.2 Hz).

Example 200

Production of Ethyl4-(3-cyanophenyl)-1-(2,4-difluorobenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (4.14 g) produced in Reference Example 20, ethylacetoacetate (5.72 g) and 2,4-difluorobenzyl amine (3.43 g), thereaction and purification were carried out in the same manner as Example185 to obtain the titled compound (2.18 g) as colorless crystals.

IR (KBr): ν 2228, 1694, 1505, 1416, 1296, 1202, 1142, 1092, 966 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.03 (3H, t, J=7.0 Hz), 2.01 (3H, s), 2.50 (3H, s),4.07 (2H, q, J=7.0 Hz), 5.10 (2H, s), 6.42-6.54 (1H, m), 6.79-6.93 (2H,m), 7.39-7.58 (4H, m).

Example 201

Production of Ethyl4-(3-cyanophenyl)-1-(4-fluorobenzyl)-5-methyl-2-(trifluoromethyl)-1H-pyrrole-3-carboxylateand Ethyl4-(3-cyanophenyl)-5-methyl-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate

By using the compound (1.13 g) produced in Reference Example 20, ethyl4,4,4-trifluoroethyl acetoacetate (2.21 g) and 4-fluorobenzyl amine(0.75 ml), the reaction and purification were carried out in the samemanner as Example 185 to obtain ethyl4-(3-cyanophenyl)-1-(4-fluorobenzyl)-5-methyl-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate(0.31 g) and ethyl4-(3-cyanophenyl)-5-methyl-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate(0.04 g) as colorless crystals.

Ethyl4-(3-cyanophenyl)-1-(4-fluorobenzyl)-5-methyl-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate

IR (KBr): ν 2230, 1725, 1512, 1264, 1202, 1159, 1119 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J=7.2 Hz), 2.04 (3H, s), 4.19 (2H, q,J=7.2 Hz), 5.25 (2H, s), 6.94-7.08 (4H, m), 7.45-7.62 (4H, m).

Ethyl4-(3-cyanophenyl)-5-methyl-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate

IR (KBr): ν 3277, 2232, 1696, 1304, 1194, 1146, 1038 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.16 (3H, t, J=7.0 Hz), 2.17 (3H, s), 4.17 (2H, q,J=7.0 Hz), 7.47-7.67 (4H, m), 9.36 (1H, br).

Example 202

Production of Methyl4-(3-cyanophenyl)-1-(4-fluorobenzyl)-2-(methoxymethyl)-5-methyl-1H-pyrrole-3-carboxylate

By using the compound (1.13 g) produced in Reference Example 20, methyl4-methoxyacetoacetate (1.75 g) and 4-fluorobenzyl amine (0.75ml), thereaction and purification were carried out in the same manner as Example185 to obtain the titled compound (0.55 g) as an oily substance.

IR (KBr): ν 2230, 1701, 1508, 1209, 1088 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.97 (3H, s), 3.37 (3H, s), 3.62 (3H, s), 4.75 (2H,s), 5.23 (2H, s), 6.91-7.06 (4H, m), 7.42-7.60 (4H, m).

Example 203

Production of Ethyl4-(4-cyanophenyl)-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate

A mixture of the compound (1.00 g) produced in Reference Example 21,4-cyanophenylboronic acid (0.46 g), tetrakis(triphenylphosphine)palladium (0.32 g), a 2M aqueous solution of sodium carbonate(8 ml) and toluene (20 ml) was hated at 90° C. for 16 hours, and cooledto room temperature. To the reaction mixture were added water and ethylacetate, and insoluble matter was filtered off. The ethyl acetate layerwas separated, washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated. The resulting crude product waspurified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) to obtain the titled compound (0.45 g) ascolorless crystals.

IR (KBr): ν 2228, 1688, 1510, 1132 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.30 (3H, t, J=7.2 Hz), 2.12 (3H, s), 2.28 (3H, s),4.26 (2H, q, J=7.2 Hz), 5.60 (2H, s), 6.95-7.00 (4H, m), 7.33 (2H, d,J=8.7 Hz), 7.69 (2H, d, J=8.7 Hz).

Example 204

Production of4-(4-cyanophenyl)-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylicacid and Ethyl4-(4-(aminocarbonyl)phenyl)-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate(0.03 g)

The compound (0.10 g) produced in Example 203 was dissolved in ethanol(0.5 ml) and tetrahydrofuran (0.3 ml), and to the solution was added 2Nsodium hydroxide (0.5 ml). The reaction mixture was stirred at roomtemperature for 5 hours, and at 50° C. for 10 hours, poured into 1Nhydrochloric acid, and extracted with ethyl acetate. The ethyl acetatelayer was dried over anhydrous magnesium sulfate and concentrated. Theresulting crude product was purified by column chromatography (carrier:silicagel, eluant: hexane-ethyl acetate) to obtain4-(4-cyanophenyl)-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylicacid (0.02 g) as colorless crystals and ethyl4-(4-(aminocarbonyl)phenyl)-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate (0.03 g) as colorless crystals.

4-(4-cyanophenyl)-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylicAcid

IR (KBr): ν 2228, 1655, 1510, 1146 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 2.31 (3H, s), 5.61 (2H, s), 6.95-7.02(4H, m), 7.32 (2H, d, J=8.1 Hz), 7.69 (2H, d, J=8.1 Hz).

Ethyl4-(4-(aminocarbonyl)phenyl)-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate(0.03 g)

IR (KBr): ν 1686, 1671, 1132 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.30 (3H, t, J=7.2 Hz), 2.12 (3H, s), 2.28 (3H, s),4.25 (2H, q, J=7.2 Hz), 5.59 (2H, s), 5.50-6.20 (2H, br), 6.94-7.01 (4H,m), 7.31 (2H, d, J=8.1 Hz), 7.84 (2H, d, J=8.1 Hz).

Example 205

Production of Benzyl1-(4-cyanobenzyl)-4-(4-cyanophenyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate

By using the compound (4.23 g) produced in Reference Example 24 and4-cyanophenylboronic acid (1.61 g), the reaction and purification werecarried out in the same manner as Example 203 to obtain the titledcompound (2.63 g) as colorless crystals.

IR (KBr): ν 2228, 1688, 1607, 1416, 1287, 1128 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.28 (3H, s), 5.23 (2H, s), 5.66 (2H,s), 7.02 (2H, d, J=8.4 Hz), 7.27-7.35 (7H, m), 7.57 (2H, d, J=8.0 Hz),7.70 (2H, d, J=8.4 Hz).

Example 206

Production of1-(4-cyanobenzyl)-4-(4-cyanophenyl)-3,5-dimethyl-1H-pyrrole-2-carboxylicAcid

The compound (2.27 g) produced in Example 205 was dissolved in ethanol(40 ml) and tetrahydrofuran (20 ml), and to the solution was added 10%palladium-carbon (1.0 g). Under hydrogen atmosphere, the reactionmixture was stirred at room temperature for 30 minutes and insolublematter was filtered off. The filtrate was concentrated to obtain thetitled compound (2.00 g) as colorless crystals.

IR (KBr): ν 2228, 1651, 1607, 1441, 1146 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.31 (3H, s), 5.69 (2H, s), 7.07 (2H, d,J=8.0 Hz), 7.34 (2H, d, J=8.0 Hz), 7.60 (2H, d, J=8.0 Hz), 7.71 (2H, d,J=8.0 Hz).

Example 207

Production of1-(4-cyanobenzyl)-4-(4-cyanophenyl)-3,5-dimethyl-1H-pyrrole-2-carboxamide

To a solution of the compound (89 mg) produced in Example 206 intetrahydrofuran (1 ml) was added thionyl chloride (0.06 ml). Thereaction mixture was stirred at room temperature for 30 minutes andconcentrated. The residue was dissolved in tetrahydrofuran (1 ml), addedto a mixed solution of 25% aqueous ammonia (1 ml) andtetrahydrofuran(0.5 ml). The reaction mixture was stirred at roomtemperature for 2 hours, poured into saturated sodium bicarbonate water,and extracted with ethyl acetate. The ethyl acetate layer was dried overanhydrous magnesium sulfate and concentrated. The resulting crudeproduct was purified by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate) to obtain the titled compound (46 mg) ascolorless crystals.

IR (KBr): ν 2228, 1653, 1605, 1437 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.10 (3H, s), 2.29 (3H, s), 5.52 (2H, br), 5.68 (2H,s), 7.09 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4Hz), 7.71 (2H, d, J=8.4 Hz).

Example 208

Production of1-(4-cyanobenzyl)-4-(4-cyanophenyl)-N,3,5-trimethyl-1H-pyrrole-2-carboxamide

By using the compound (80 mg) produced in Example 206 as a startingmaterial and 33% methylamine ethanol solution (1 ml) as an aminecomponent, the reaction and purification were carried out in the samemanner as Example 207 to obtain the titled compound (52 m g) ascolorless crystals.

IR (KBr): ν 2228, 1636, 1607, 1530, 729 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.07 (3H, s), 2.22 (3H, s), 2.93 (3H, d, J=4.8 Hz),5.59 (2H, s), 5.65 (1H, br), 7.09 (2H, d, J=8.7 Hz), 7.31 (2H, d, J=8.1Hz), 7.58 (2H, d, J=Hz), 7.69 (2H, d, J=8.7 Hz).

Example 209

Production of1-(4-cyanobenzyl)-4-(4-cyanophenyl)-N,N,3,5-tetramethyl-1H-pyrrole-2-carboxamide

By using the compound (80 mg) produced in Example 206 as a startingmaterial and 50% dimethylamine solution (1 ml) as an amine component,the reaction and purification were carried out in the same manner asExample 207 to obtain the titled compound (35 m g) as colorlesscrystals.

IR (KBr): ν 2226, 1607, 1697, 1111, 731 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.01 (3H, s), 2.14 (3H, s), 2.96 (6H, s), 5.00-5.50(2H, br), 7.13 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.4 Hz), 7.60 (2H, d,J=8.4 Hz), 7.67 (2H, d, J=8.4 Hz).

Example 210

Production of4-(1-(4-cyanobenzyl)-2,4-dimethyl-5-(4-morpholinylcarbonyl)-1H-pyrrole-3-yl)benzonitrile

To a solution of the compound (80 mg) produced in Example 206 intetrahydrofuran (1 ml) was added thionyl chloride (0.06 ml). Thereaction mixture was stirred at room temperature for 30 minutes andconcentrated. The residue was dissolved in tetrahydrofuran (1 ml) andadded to a solution of morpholine (44 mg) and triethylamine (0.083 ml)in tetrahydrofuran (0.5 ml). The reaction mixture was stirred at roomtemperature for 16 hours, poured into water and extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous magnesiumsulfate and concentrated. The resulting crude product was purified bycolumn chromatography (carrier: silicagel, eluant: hexane-ethyl acetate)to obtain the titled compound (81 mg) as colorless crystals.

IR (KBr): ν 2226, 1607, 1433, 1115, 731 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 2.18 (3H, s), 3.00-3.75 (8H, m),5.20-5.45 (2H, br), 7.12 (2H, d, J=8.7 Hz), 7.34 (2H, d, J=8.7 Hz), 7.62(2H, d, J=8.7 Hz), 7.68 (2H, d, J=8.7 Hz).

Example 211

Production of1-(4-cyanobenzyl)-4-(4-cyanophenyl)-3,5-dimethyl-N-(3-pyridinyl)-1H-pyrrole-2-carboxamide

To a solution of the compound (80 mg) produced in Example 206,3-aminopyridine (47 mg) and triethylamine (0.047 ml) indimethylformamide (1 ml) was added cyanide diethylphosphate (0.041 ml)and the reaction mixture was stirred at room temperature for 18 hoursand at 70° C. for 6 hours. The reaction mixture was poured into water,and extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated brine, dried over magnesium sulfate and concentrated. Theresidue was purified by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate) to obtain the titled compound (29 mg) ascolorless crystals.

IR (KBr): ν 2222, 1655, 1603, 1541, 1424, 845 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.37 (3H, s), 5.63 (2H, s), 7.13 (2H, d,J=7.8 Hz), 7.25-7.29 (1H, m), 7.35 (2H, d, J=8.4 Hz), 7.48 (1H, s), 7.60(2H, d, J=7.8 Hz), 7.72 (2H, d, J=8.4 Hz), 8.12-8.15 (1H, m), 8.34 (1H,d, J=4.5 Hz), 8.55-8.56 (1H, m).

Example 212

Production of Benzyl4-(4-cyanophenyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate

By using the compound (3.38 g) produced in Reference Example 23 and4-cyanophenylboronic acid (1.76 g), the reaction and purification werecarried out in the same manner as Example 203 to obtain the titledcompound (1.14 g) as colorless crystals.

IR (KBr): ν 3301, 2226, 1665, 1609, 1433, 1269, 1096 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.26 (3H, s), 2.31 (3H, s), 5.33 (2H, s), 7.31-7.44(7H, m), 7.68 (2H, d, J=8.7 Hz), 8.80 (1H, br).

Example 213

Production of 4-(4-cyanophenyl)-3,5-dimethyl-1H-pyrrole-2-carboxylicAcid

By using the compound (1.12 g) produced in Example 212, the reaction andpurification were carried out in the same manner as Example 206 toobtain the titled compound (0.62 g) as colorless crystals.

IR (KBr): ν 2919, 2226, 1651, 1252 cm⁻¹.

¹H-NMR (CDCl₃+CD₃OD) δ: 2.27 (3H, s), 2.31 (3H, s), 7.36 (2H, d, J=8.4Hz), 7.68 (2H, d, J=8.4 Hz).

Example 214

Production of4-(4-cyanophenyl)-3,5-dimethyl-N-(3-pyridinyl)-1H-pyrrole-2 -carboxamide

The compound (72 mg) produced in Example 213, 3-aminopyridine (57 mg)and triethylamine (0.056 ml) were dissolved in dimethylformamide (1 ml)and to the solution were added 1-hydroxybenzotriazole (55 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg) .The reaction mixture was stirred at room temperature for 18 hours and at60° C. for 72 hours. The reaction mixture was poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried over magnesium sulfate and concentrated. Theresidue was purified by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate) to obtain the titled compound (9 mg) as acolorless powder.

IR (KBr): ν 2226, 1638, 1605, 1483, 1445, 1426, 1381, 1325 cm⁻¹.

¹H-NMR (CDCl₃+CD₃OD) δ: 2.31 (3H, s), 2.40 (3H, s), 7.32-7.40 (3H, m),7.72 (2H, d, J=8.4 Hz), 8.25-8.52 (3H, m).

Example 215

Production of Ethyl4-(4-cyanophenyl)-2-(4-fluorobenzyl)-5-methyl-1H-pyrrole-3-carboxylate

By using the compound (1.88 g) produced in Reference Example 25 andethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.48 g), the reaction andpurification were carried out in the same manner as Example 1 to obtainthe titled compound (0.21 g) as pale yellow solids.

IR (KBr): ν 2226, 1694, 1607, 1508, 1225, 1159, 841 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.06 (3H, t, J=6.9 Hz), 2.06 (3H, s), 4.09 (2H, q,J=6.9 Hz), 4.29 (2H, s), 6.98-7.04 (2H, m), 7.20-7.26 (2H, m), 7.35 (2H,d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 8.13 (1H, br).

Example 216

Production of4-(1-(4-cyanobenzyl)-5-(hydroxymethyl)-2,4-dimethyl-1H-pyrrol-3-yl)benzonitrile

The compound (0.22 g) produced in Example 206 and N-ethyldiisopropylamine (0.13 ml) was dissolved in tetrahydrofuran (5 ml), andto the solution was added benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (0.31 g) The reactionmixture was stirred at room temperature for 30 minutes and to thereaction mixture was added sodium boron hydride (55 mg). The reactionmixture was further stirred at room temperature for 18 hours, pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried over magnesium sulfate andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) to obtain the titledcompound (0.03 g) as colorless crystals.

IR (KBr): ν 3495, 2226, 1605, 733, 550 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.49 (1H, br), 2.10 (6H, s), 4.53 (2H, s), 5.30 (2H,s), 7.04 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.61 (2H, d, J=8.4Hz), 7.66 (2H, d, J=8.4 Hz).

Example 217

Production of Tert-butyl3-(4-cyanophenyl)-4-methyl-1H-pyrrole-2-carboxylate

To a mixture of the compound (1.88 g) produced in Reference Example 25,tert-butyl isocyanoacetate (1.55 g), tetrahydrofuran (10 ml) andisopropyl alcohol (10 ml) was added N,N,N′,N′-tetramethyl guanidine(1.84 g). The reaction mixture was stirred at 60° C. for 2 hours, pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried over magnesium sulfate andconcentrated. The residue was washed with diisoprpyl ether to obtain thetitled compound (2.25 g) as pale brown crystals.

IR (KBr): ν 3287, 2226, 1667, 1393, 1291, 1155 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.34 (9H, s), 1.96 (3H, s), 6.75-6.77 (1H, m), 7.42(2H, d, J=8.4 Hz), 7.65 (2H, d, J=8.4 Hz), 8.99 (1H, br).

Example 218

Production of Tert-butyl3-(4-cyanophenyl)-4-methyl-1-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate

A suspension of sodium hydride (60% oil suspension, 0.64 g) indimethylformamide (20 ml) was cooled in an ice bath, and to thesuspension was added 3-chloromethylpyridine hydrochloride (0.95 g). Thereaction mixture was stirred at the same temperature for 10 minutes. Tothe reaction mixture was added the compound (1.50 g) produced in Example217, and the reaction mixture was stirred at room temperature for 2hours and at 60° C. for 18 hours. The reaction mixture was poured intowater and extracted with ethyl acetate. The ethyl acetate layer waswashed with water and saturated brine, successively, dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: hexane-ethyl acetate) toobtain the titled compound (1.12 g) as colorless crystals.

IR (KBr): ν 2226, 1692, 1368, 1304, 1161, 1088 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.87 (3H, s), 5.52 (2H, s), 6.70 (1H,s), 7.23-7.35 (3H, m), 7.48-7.51 (1H, m), 7.63-7.67 (2H, m), 8.45 (1H,dd, J=2.1, 0.6 Hz), 8.52 (1H, dd, J=4.8, 1.5 Hz).

Example 219

Production of4-(4-methyl-1-(3-pyridinylmethyl)-1H-pyrrol-3-yl)benzonitrile

The compound (61 mg) produced in Example 218 was dissolved in TFA (0.5ml) and the solution was stirred at room temperature for 16 hours. Thereaction mixture was concentrated, diluted with saturated sodiumbicarbonate water, and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate and concentrated. The resultingresidue was purified by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate) to obtain the titled compound (15 mg) ascolorless crystals.

IR (KBr): ν 2222, 1605, 1541, 1427, 1412, 1152, 843, 787, 712 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.22 (3H, s), 5.04 (2H, s), 6.53-6.54 (1H, m), 6.85(1H, d, J=2.4 Hz), 7.25-7.28 (1H, m), 7.44-7.62 (5H, m), 8.50 (1H, s),8.56 (1H, d, J=3.6 Hz).

Example 220

Production of Ethyl4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

To solution of the compound (0.89 g) produced in Example 103 intetrahydrofuran (10 ml) were added thionyl chloride (0.80 ml) anddimethylformamide (0.025 ml). The mixture was stirred at roomtemperature for 2 hours and concentrated. The residue was dissolved intetrahydrofuran (5 ml), and to the solution was added ethanol (16 ml).The reaction mixture was stirred at room temperature for 2 hours andconcentrated. The residue was dissolved in saturated sodium bicarbonatewater and ethyl acetate. The ethyl acetate layer was separated, driedover anhydrous magnesium sulfate and concentrated to obtain the titledcompound (0.97 g) as colorless crystals.

IR (KBr): ν 3301, 2226, 1671, 1607, 1435, 1294, 1175, 1094 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.09 (3H, t, J=7.0 Hz), 2.13 (3H, s), 2.53 (3H, s),4.10 (2H, q, J=2.0 Hz), 7.35 (2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0 Hz),7.98 (1H, br).

Example 221

Production of Ethyl4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carboxylate

A suspension of sodium hydride (60% oil suspension, 0.35 g) indimethylformamide (8 ml) was cooled in an ice bath, and to thesuspension was added 3-chloromethylpyridine hydrochloride (0.53 g), andthe reaction mixture was stirred at the same temperature for 10 minutes.To the reaction mixture was added a solution of the compound (0.77 g)produced in Example 220 in dimethylformamide(6 ml). The reaction mixturewas stirred at room temperature for 4 hours, poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, saturated brine, successively, dried over magnesium sulfate andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) to obtain the titledcompound (0.94 g) as colorless crystals.

IR (KBr): ν 2224, 1694, 1292, 1157 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.04 (3H, t, J=7.0 Hz), 2.03 (3H, s), 2.51 (3H, s),4.08 (²H, q, J=7.0 Hz), 5.15 (2H, s), 7.17-7.37 (4H, m), 7.63 (2H, d,J=8.0 Hz), 8.37 (1H, d, J=1.4 Hz), 8.56 (1H, dd, J=4.4, 1.4 Hz).

Example 222

Production of Isopropyl4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (1.03 g) produced in Example 103 as a startingmaterial and isopropyl alcohol (16 ml) as an alcohol component, thereaction and purification were carried out in the same manner as Example220 to obtain the titled compound (0.74 g) as colorless crystals.

IR (KBr): ν 3303, 2226, 1669, 1607, 1435, 1292, 1171, 1092 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.09 (6H, d, J=6.2 Hz), 2.12 (3H, s), 2.53 (3H, s),5.10 (1H, septet, J=6.2 Hz), 7.35 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.4Hz), 7.97 (1H, br).

Example 223

Production of Isopropyl4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carboxylate

By using the compound (0.64 g) produced in Example 222, the reaction andpurification were carried out in the same manner as Example 221 toobtain the titled compound (0.64 g) as colorless crystals.

IR (KBr): ν 2224, 1694, 1291, 1165, 1109 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.04 (6H, d, J=6.2 Hz), 2.02 (3H, s), 2.51 (3H, s),5.00 (1H, septet, J=6.2 Hz), 5.14 (2H, s), 7.19-7.37 (4H, m), 7.63 (2H,d, J=8.0 Hz), 8.37 (1H, d, J=1.4 Hz), 8.56 (1H, dd, J=4.4, 1.4 Hz).

Example 224

Production of Ethyl4-(4-bromophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (20.00 g) produced in Reference Example 26, thereaction and purification were carried out in the same manner as Example1 to obtain the titled compound (16.46 g) as colorless crystals.

IR (KBr): ν 3304, 1674, 1433, 1291, 1173, 1094 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.10 (3H, t, J=7.2 Hz), 2.10 (3H, s), 2.51 (3H, s),4.09 (2H, q, J=7.2 Hz), 7.11 (2H, d, J=8.1 Hz), 7.44 (2H, d, J=8.1 Hz),7.92 (1H, br).

Example 225

Production of5-(4-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-3-methyl-1,2,4-oxadiazole

A suspension of sodium hydride (60% oil suspension, 1.20 g) intetrahydrofuran (50 ml) was heated to 70° C., and to the suspension wasadded acetamide oxime (2.22 g). The reaction mixture was stirred at thesame temperature for 1 hour. To the reaction mixture was added thecompound (4.51 g) produced in Example 224, and the reaction mixture washeated for 20 hours under reflux. The reaction mixture was cooled toroom temperature, and insoluble matter was filtered off. The filtrate ofthe tetrahydrofuran layer was washed with saturated brine, dried overmagnesium sulfate and concentrated. The residue was recrystallized fromethyl acetate to obtain the titled compound (3.00 g) as colorlesscrystals.

IR (KBr): ν 3256, 1576, 1399, 1345 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 2.34 (3H, s), 2.58 (3H, s), 7.12 (2H, d,J=8.8 Hz), 7.47 (2H, d, J=8.8 Hz), 8.22 (1H, br).

Example 226

Production of4-(2,5-dimethyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrol-3-yl)benzonitrile

Under nitrogen atmosphere, a mixture of the compound (2.80 g) producedin Example 225, zinc cyanide (2.00 g),tris(dibenzylideneacetone)dipalladium (0.73 g),1,1′-bis(diphenylphosphino)ferrocene (0.44 g) and dimethylformamide (30ml) was stirred at 80° C. for 18 hours and at 120° C. for 24 hours. Thereaction mixture was cooled to room temperature and diluted with ethylacetate and water. Insoluble matter was filtered off, and the ethylacetate layer, which was separated from the filtrate, was washed withwater and saturated brine, successively, dried over magnesium sulfateand concentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) to obtain the titledcompound (0.22 g) as colorless crystals.

IR (KBr): ν 3301, 2228, 1609, 1584, 1402, 1346 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.33 (3H, s), 2.61 (3H, s), 7.35 (2H, d,J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz), 8.11 (1H, br).

Example 227

Production of4-(2,5-dimethyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(3-pyridinylmethyl)-1H-pyrrol-3-yl)benzonitrile

By using the compound (0.19 g) produced in Example 221, the reaction andpurification were carried out in the same manner as Example 225 toobtain the titled compound(0.10 g) as colorless crystals.

IR (KBr): ν 2226, 1588, 1410, 1337, 735 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 2.34 (3H, s), 2.60 (3H, s), 5.21 (2H,s), 7.21-7.38 (4H, m), 7.65 (2H, d, J=8.4 Hz), 8.40 (1H, d, J=1.8 Hz),8.57 (1H, dd, J=4.6, 1.8 Hz).

Example 228

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((1-trityl-1H-imidazol-2-yl)methyl)-1H-pyrrole-3-carbonitrile

By using the compound (0.30 g) produced in Example 105 and the compound(0.68 g) produced in Reference Example 28, the reaction and purificationwere carried out in the same manner as Reference Example 24 to obtainthe titled compound (0.37 g) as colorless crystals.

IR (KBr): ν 2215, 1609, 1447, 1426, 733, 704 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.04 (3H, s), 3.96 (2H, s), 6.96 (2H,s), 7.21-7.48 (17H, m), 7.64 (2H, d, J=8.4 Hz).

Example 229

Production of4-(4-cyanophenyl)-1-(1H-imidazol-2-ylmethyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

A mixture of the compound (0.36 g) produced in Example 228, pyridinehydrochloride (0.12 g) and methanol (3 ml) was heated at 70° C. for 1hour and concentrated. The residue was dissolved in ethyl acetate and 1Nhydrochloric acid, and the aqueous layer was separated. The aqueouslayer was neutralized with saturated sodium bicarbonate water andextracted with ethyl acetate. The obtained ethyl acetate layer was driedover magnesium sulfate and concentrated. The residue was recrystallizedform ethyl acetate to obtain the titled compound (0.16 g) as colorlesscrystals.

IR (KBr): ν 2222, 1607 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.26 (3H, s), 2.43 (3H, s), 5.20 (2H, s), 7.00 (1H,s), 7.10 (1H, s), 7.47 (2H, d, J=8.4 Hz), 7.68 (2H, d, J=8.4 Hz), 8.83(1H, br).

Example 230

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrrole-3-carbonitrile

To a mixture of the compound (60 mg) produced in Example 229, potassiumcarbonate (55 mg) and dimethylformamide (2 ml) was added methyl iodide(0.013 ml). The reaction mixture was stirred at room temperature for 14hours, diluted with water and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried over magnesiumsulfate and concentrated. The residue was purified by columnchromatography (carrier: silicagel, eluant: ethyl acetate-methanol) toobtain the titled compound (36 mg) as colorless crystals.

IR (KBr): ν 2213, 1607, 1427, 735 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 2.41 (3H, s), 3.60 (3H, s), 5.12 (2H,s), 6.89 (1H, d, J=1.2 Hz), 6.99 (1H, d, J=1.2 Hz), 7.54 (2H, d, J=8.4Hz), 7.68 (2H, d, J=8.4 Hz).

Example 231

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((1-trityl-1H-imidazol-4-yl)methyl)-1H-pyrrole-3-carbonitrile

By using the compound (0.30 g) produced in Example 105 and the compound(1.10 g) produced in Reference Example 29, reaction and purificationwere carried out in the same manner as Reference Example 24 to obtainthe titled compound (0.31 g) as colorless crystals.

IR (KBr): ν 2213, 1607, 1445, 743, 702 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 2.43 (3H, s), 4.94 (2H, s), 6.55 (1H,s), 7.08-7.15 (6H, m), 7.30-7.37 (9H, m), 7.42-7.47 (3H, m), 7.67 (2H,d, J=8.8 Hz).

Example 232

Production of4-(4-cyanophenyl)-1-(1H-imidazol-4-ylmethyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

By using the compound (0.29 g) produced in Example 231, the reaction andpurification were carried out in the same manner as Example 229 toobtain the titled compound (0.15 g) as colorless crystals.

IR (KBr): ν 2226, 2213, 1607, 855 cm⁻¹.

¹H-NMR (CDCl₃+DMSO-d₆) δ: 2.34 (3H, s), 2.49 (3H, s), 5.03 (2H, s), 6.68(1H, s), 7.48-7.56 (3H, s), 7.68 (2H, d, J=8.4 Hz).

Example 233

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((1-methyl-1H-imidazol-4-yl)methyl)-1H-pyrrole-3-carbonitrileand4-(4-cyanophenyl)-2,5-dimethyl-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrrole-3-carbonitrile

By using the compound (80 mg) produced in Example 232, the reaction andpurification were carried out in the same manner as Example 230 toobtain4-(4-cyanophenyl)-2,5-dimethyl-1-((1-methyl-1H-imidazol-4-yl)methyl)-1H-pyrrole-3-carbonitrile(63 mg) and4-(4-cyanophenyl)-2,5-dimethyl-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrrole-3-carbonitrile (3 mg) as colorless crystals.

4-(4-cyanophenyl)-2,5-dimethyl-1-((1-methyl-1H-imidazol-4-yl)methyl)-1H-pyrrole-3-carbonitrile

IR (KBr): ν 2213, 1607, 1541, 1507, 1427, 831, 735 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.33 (3H, s), 2.48 (3H, s), 3.65 (3H, s), 4.99 (2H,s), 6.56 (1H, s), 7.39 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.68 (2H, d,J=8.4 Hz).

4-(4-cyanophenyl)-2,5-dimethyl-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrrole-3-carbonitrile

IR (KBr): ν 2215, 1607, 1539, 1507, 1427, 833, 737 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 2.42 (3H, s), 3.61 (3H, s), 5.04 (2H,s), 6.57 (1H, s), 7.47-7.52 (3H, m), 7.71 (2H, d, J=8.4 Hz).

Example 234

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((1-trityl-1H-1,2,3-triazo1-4-yl)methyl)-1H-pyrrole-3-carbonitrile

By using the compound (0.13 g) produced in Example 105 and the compound(0.27 g) produced in Reference Example 30, the reaction and purificationwere carried out in the same manner as Reference Example 24 to obtainthe titled compound (0.26 g) as colorless crystals.

IR (KBr): ν 2215, 1609, 1445, 745, 700 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.24 (3H, s), 2.40 (3H, s), 5.12 (2H, s), 7.05-7.35(15H, m), 7.42-7.47 (3H, m), 7.69 (2H, d, J=8.4 Hz).

Example 235

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-(1H-1,2,3-triazol-4-ylmethyl)-1H-pyrrole-3-carbonitrile

To a mixture of the compound (0.25 g) produced in Example 234, anisole(0.2 ml) and dichloromethane (4 ml) was added TFA (2 ml), and thereaction mixture was stirred at room temperature for 10 minutes. Thereaction mixture was concentrated, and the residue was dissolved inethyl acetate and saturated sodium bicabonate water. The ethyl acetatelayer was dried over magnesium sulfate and concentrated. The resultingresidue was purified by column chromatography (carrier: silicagel,eluant: hexane-ethyl acetate) and recrystallized from ethylacetate-hexane to obtain the titled compound (0.03 g) as colorlesscrystals.

IR (KBr): ν 3196, 2220, 1607, 1541, 1427, 735 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.32 (3H, s), 2.49 (3H, s), 5.21 (2H, s), 7.46-7.52(3H, m), 7.68 (2H, d, J=8.4 Hz).

Example 236

Production of Ethyl(3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)acetate

By using the compound (0.33 g) produced in Example 105 and bromoethylacetate (0.20 ml), the reaction and purification were carried out in thesame manner as Reference Example 24 to obtain the titled compound (0.16g) as colorless crystals.

IR (KBr): ν 2216, 1748, 1609, 1427, 1372, 1208, 1024, 833 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.0 Hz), 2.23 (3H, s), 2.39 (3H, s),4.28 (2H, q, J=7.0 Hz), 4.59 (2H, s), 7.50 (2H, d, J=8.4 Hz), 7.70 (2H,d, J=8.4 Hz).

Example 237

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carbonitrile

By using the compound (0.12 g) produced in Example 236, the reaction andpurification were carried out in the same manner as Example 225 toobtain the titled compound (0.06 g) as colorless crystals.

IR (KBr): ν 2218, 1609, 1426, 1327, 735 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.34 (3H, s), 2.42 (3H, s), 2.51 (3H, s), 5.25 (2H,s), 7.49 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.4 Hz).

Example 238

Production of Tert-butyl4-(4-cyanophenyl)-1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrrol-2-ylcarbamate

By using the compound (0.82 g) produced in Reference Example 32, thereaction and purification were carried out in the same manner as Example203 to obtain the titled compound (0.53 g) as colorless crystals.

IR (KBr): ν 3266, 2224, 1694, 1510, 1281, 1159, 829 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.99 (3H, s), 2.11 (3H, s), 4.99 (2H,s), 5.72 (1H, br), 6.98-7.00 (4H, m), 7.35 (2H, d, J=8.1 Hz), 7.64 (2H,d, J=8.1 H).

Example 239

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-(1-(3-pyridinyl)ethyl)-1H-pyrrole-3-carbonitrile

By using the compound (0.34 g) produced in Example 105 and the compound(0.50 g) produced in Reference Example 33, the reaction and purificationwere carried out in the same manner as Reference Example 24 to obtainthe titled compound (0.22 g) as colorless crystals.

IR (KBr): ν 2216, 1607, 1424, 729 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.99 (3H, d, J=7.2 Hz), 2.15 (3H, s), 2.31 (3H, s),5.67 (1H, q, J=7.2 Hz), 7.30-7.43 (2H, m), 7.50 (2H, d, J=8.4 Hz), 7.69(2H, d, J=8.4 Hz), 8.44 (1H, d, J=1.8 Hz), 8.59 (1H, dd, J=4.4, 1.8 Hz).

Example 240

Production of Ethyl(3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl)(3-pyridinyl)acetate

By using the compound (0.66 g) produced in Example 105 and ethylbromo-(3-pyridyl)acetate (1.20 g), the reaction and purification werecarried out in the same manner as Reference Example 24 to obtain thetitled compound (0.16 g) as colorless crystals.

IR (KBr): ν 2220, 1748, 1609, 1424, 1200, 1022, 733 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.0 Hz), 2.15 (3H, s), 2.30 (3H, s),4.41 (2H, q, J=7.0 Hz), 6.19 (1H, s), 7.30-7.54 (4H, m), 7.71 (2H, d,J=8.4 Hz), 8.43 (1H, d, J=2.6 Hz), 8.64 (1H, dd, J=4.8, 1.4 Hz).

Example 241

Production of4-(4-cyanophenyl)-2,5-dimethyl-1-(4-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

A mixture of the compound (89 mg) produced in Example 105, 4-pyridylmethanol (87 mg), (tributylphosphoranylidene)acetonitrile (0.19 g) andtoluene (3 ml) was heated at 110° C. for 14 hours and concentrated. Theresidue was purified by column chromatography (carrier: silicagel,eluant: ethyl acetate-methanol) and recrystallized from ethyl acetate toobtain the titled compound (4 mg) as colorless crystals.

IR (KBr): ν 2215, 1607, 1416 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.36 (3H, s), 5.11 (2H, s), 6.85 (2H, d,J=6.0 Hz), 7.52 (2H, d, J=8.4 Hz), 7.71. (2H, d, J=8.4 Hz), 8.61 (2H, d,J=6.0 Hz).

Example 242

Production of Methyl 4-(4-cyanophenyl)-2-methyl-1H-pyrrole-3-carboxylate

To a suspension of powdery potassium hydroxide (3.16 g) intetrahydrofuran (120 ml) was added dropwise methyl acetoacetate (17.8ml). The reaction mixture was stirred at the same temperature for 30minutes and cooled to 0° C. To the mixture was added the compound (9.56g) produced in Reference Example 27, and the reaction mixture wasstirred at 0° C. for 30 minutes. The reaction mixture was poured intowater, extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated brine, dried over magnesium sulfate and concentrated. Tothe residue were added methanol (80 ml), water (16 ml) and concentratedhydrochloric acid (1.2 ml), and the reaction mixture was heated for 2hours under reflux. The reaction mixture was concentrated, diluted withsaturated sodium bicarbonate water and extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried overmagnesium sulfate and concentrated. The residue was dissolved in 20%solution of ammonia in methanol. The solution was stirred at roomtemperature for 40 hours and concentrated. The residue was purified bycolumn chromatography (carrier: silicagel, eluant: hexane-ethyl acetate)to obtain the titled compound (2.00 g) as yellow crystals.

IR (KBr): ν 3304, 2226, 1682, 1607, 1447, 1296, 1130, 845, 791, 731cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 3.70 (3H, s), 6.64 (1H, d, J=2.4 Hz),7.44-7.49 (2H, m), 7.57-7.62 (2H, m), 8.29 (1H, br).

Example 243

Production of Benzyl 4-(4-cyanophenyl)-2-methyl-1H-pyrrole-3-carboxylate

To a mixture of the compound (26.00 g) produced in Reference Example 27,benzyl acetoacetate (29.40 g) and methanol (35 ml) was added sodiummethoxide (2.03 g), and the reaction mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added 20% solutionof ammonia in methanol, and the reaction mixture was further stirred atroom temperature for 14 hours and concentrated. To the residue wereadded saturated brine and ethyl acetate, and the ethyl acetate layer wasseparated. The ethyl acetate layer was dried over magnesium sulfate andconcentrated. The residue was purified by column chromatography(carrier: silicagel, eluant: hexane-ethyl acetate) to obtain the titledcompound (15.20 g) as yellow crystals.

IR (KBr): ν 2226, 1680, 1607, 1439, 1292, 1113 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.56 (3H, s), 5.16 (2H, s), 6.62 (1H, d, J=2.6 Hz),7.14-7.50 (9H, m), 8.29 (1H, br).

Example 244

Production of 4-(4-cyanophenyl)-2-methyl-1H-pyrrole-3-carboxylic Acid

The compound (15.10 g) produced in Example 243 was dissolved in methanol(200 ml) and tetrahydrofuran (100 ml), and to the solution was added 10%palladium-carbon (3.0 g). Under hydrogen atmosphere, the reactionmixture was stirred at room temperature for 3 hours. Insoluble matterwas filtered off, and the filtrate was concentrated to obtain the titledcompound (10.50 g) as colorless crystals.

IR (KBr): ν 3295, 2234, 1661, 1607, 1464, 1310, 1146, 843 cm⁻¹.

¹H-NMR (200 MHz, DMSO-d₆) δ: 2.36 (3H, s), 6.81 (1H, d, J=2.2 Hz), 7.48(2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz), 11.39 (1H, br).

Example 245

Production of 4-(4-cyanophenyl)-2-methyl-1H-pyrrole-3-carboxamide

By using the compound (10.40 g) produced in Example 244, the reactionand purification were carried out in the same manner as Example 92 toobtain the titled compound (7.01 g) as colorless crystals.

IR (KBr): ν 3333, 2224, 1638, 1605, 839 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 5.10-5.40 (2H, m), 6.68 (1H, d, J=2.6Hz), 7.53 (2H, d, J=8.8 Hz), 7.65 (2H, d, J=8.8 Hz), 8.28 (1H, br).

Example 246

Production of 4-(4-cyanophenyl)-2-methyl-1H-pyrrole-3-carbonitrile

By using the compound (7.00 g) produced in Example 245, the reaction andpurification were carried out in the same manner as Example 105 toobtain the titled compound (2.97. g) as colorless crystals.

IR (KBr): ν 3301, 2222, 1607 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 6.94 (1H, d, J=2.4 Hz), 7.66 (2H, d,J=8.8 Hz), 7.74 (2H, d, J=8.8 Hz), 8.46 (1H, br).

Example 247

Production of4-(4-cyanophenyl)-2-methyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

By using the compound (1.82 g) produced in Example 246, the reaction andpurification were carried out in the same manner as Example 221 toobtain the titled compound (2.11 g) as colorless crystals.

IR (KBr): ν 2926, 2220, 1609, 1427 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 5.12 (2H, s), 6.89 (1H, s), 7.33-7.35(2H, m), 7.65 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 8.48 (1H, s),8.60-8.64 (1H, m).

Example 248

Production of4-(4-cyanophenyl)-1-(2-hydroxy-2-(3-pyridinyl)ethyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile

A suspension of sodium hydride (60% oil suspension, 80 mg) in.dimethylformamide (5 ml) was cooled in an ice bath, and to thesuspension was added the compound (0.40 g) produced in Example 105. Thereaction mixture was stirred at the same temperature for 10 minutes. Tothe reaction mixture was added 3-(2-oxylanyl)pyridine (0.44 g), and thereaction mixture was stirred at room temperature for 16 hours and at 60°C. for 3 hours. The reaction mixture was poured into water, extractedwith ethyl acetate. The ethyl acetate layer was washed with water andsaturated brine, dried over magnesium sulfate and concentrated. Theresidue was purified by column chromatography (carrier: silicagel,eluant: ethyl acetate-methanol) to obtain the titled compound (0.17 g)as colorless crystals.

IR (KBr): ν 2213, 1609, 1426 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 2.43 (3H, s), 2.51 (1H, d, J=3.6 Hz),3.96-4.19 (2H, m), 4.99-5.08 (1H, m), 7.36 (1H, dd, J=7.6, 5.2 Hz), 7.47(2H, d, J=8.4 Hz), 7.66-7.72 (3H, m), 8.60-8.65 (2H, m).

Example 249

Production of Ethyl4-(4-cyanophenyl)-2-(4-fluorobenzyl)-1,5-dimethyl-1H-pyrrole-3-carboxylate

By using the compound (0.13 g) produced in Example 215 and methyl iodide(0.022 ml), the reaction and purification were carried out in the samemanner as Reference Example 24 to obtain the titled compound (0.05 g) ascolorless crystals.

IR (KBr): ν 2226, 1692, 1607, 1508, 1291, 1221, 1190, 1154, 1042, 839cm⁻¹.

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.2 Hz), 2.08 (3H, s), 3.35 (3H, s),4.12 (2H, q, J=7.2 Hz), 4.41 (2H, s), 6.97 (2H, t, J=8.7 Hz), 7.14 (2H,dd, J=8.7, 5.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz).

Example 250

Production of4-(4-cyanophenyl)-5-formyl-2-methyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

Dimethylformamide (5 ml) was cooled in an ice bath, and phosphorousoxychloride (0.98 ml) was added. The reaction mixture was stirred for 30minutes, and to the reaction mixture was added the compound (1.00 g)produced in Example 247. The reaction mixture was stirred at 80° C. for14 hours, poured into water. The reaction mixture was neutralized withsaturated sodium bicarbonate water and extracted with ethyl acetate. Theethyl acetate layer was washed with water and saturated brine,successively, dried over magnesium sulfate and concentrated. The residuewas purified by column chromatography (carrier: silicagel, eluant:hexane-ethyl acetate) to obtain the titled compound (0.30 g) ascolorless crystals.

IR (KBr): ν 2228, 1663, 1478, 1429, 866 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.51 (3H, s), 5.73 (2H, s), 7.29-7.43 (2H, m), 7.62(2H, d, J=8.8 Hz), 7.81 (2H, d, J=8.8 Hz), 8.40 (1H, d, J=1.6 Hz), 8.58(1H, dd, J=4.8, 1.6 Hz), 9.51 .(1H, s).

Example 251

Production of4-(4-cyanophenyl)-5-(hydroxymethyl)-2-methyl-1-(3-pyridinylmethyl)-1H-pyrrole-3-carbonitrile

The compound (51 mg) produced in Example 250 was dissolved in methanol(1.5 ml) and tetrahydrofuran (0.5 ml), and to the solution was addedsodium boron hydride (8 mg). The reaction mixture was stirred at roomtemperature for 30 minutes and concentrated. The residue was dilutedwith saturated brine and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate and concentrated to obtain thetitled compound (50 mg) as colorless crystals.

IR (KBr): ν 3202, 2224, 1609, 1427, 1024, 862, 710, 559 cm⁻¹.

¹H-NMR (CDCl₃+DMSO-d₆) δ: 2.35 (3H, s), 4.45 (2H, d, J=4.8 Hz), 4.63(1H, t, J=4.8 Hz), 5.36 (2H, s), 7.28-7.31 (2H, m), 7.67 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.8 Hz), 8.39 (1H, s), 8.56 (1H, t, J=3.4 Hz).

Formulas of the compounds produced in Reference Examples and Examplesmentioned above are shown in the following tables 1 to 31. TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

TABLE 7

TABLE 8

TABLE 9

TABLE 10

TABLE 11

Example 76

Example 77

Example 78

Example 79

Example 80

Example 81

Example 82

Example 83

Example 84

TABLE 12

Example 85

Example 86

Example 87

Example 88

Example 88

Example 89

Example 90

Example 91

Example 92

TABLE 13

Example 93

Example 94

Example 95

Example 96

Example 97

Example 98

Example 98

Example 100

Example 101

TABLE 14

Example 102

Example 103

Example 104

Example 105

Example 106

Example 107

Example 108

Example 109

Example 110

TABLE 15

Example 111

Example 112

Example 113

Example 114

Example 115

Example 116

Example 117

Example 118

Example 119

TABLE 16

Example 120

Example 121

Example 122

Example 123

Example 124

Example 125

Example 126

Example 127

Example 128

TABLE 17

Example 129

Example 130

Example 131

Example 132

Example 133

Example 134

Example 135

Example 136

Example 137

Example 138

Example 139

Example 140

TABLE 18

Example 141

Example 142

Example 143

Example 144

Example 145

Example 146

Example 147

Example 148

Example 149

TABLE 19

Example 150

Example 151

Example 152

Example 153

Example 154

Example 155

Example 156

Example 157

Example 158

TABLE 20

Example 159

Example 160

Example 161

Example 162

Example 163

Example 164

Example 165

Example 166

Example 167

TABLE 21

TABLE 22

TABLE 23

TABLE 24

TABLE 25

TABLE 26

TABLE 27

TABLE 28

TABLE 29

TABLE 30

TABLE 31

Example 250

Example 251

Pharmaceutical Preparation 1 (1) Compound of Example 4  5.0 mg (2)Sodium chloride 20.0 mg (3) Distilled water To make total amount 2 ml

The compound of Example 4 (5.0 mg) and sodium chloride (20.0 mg) aredissolved in distilled water, and to the solution is added water to makethe total volume 2 ml. The solution is filtered, and filled into anampoule (content: 2 ml) under sterilized conditions. The ampoule issterilized and sealed to obtain an injectable solution.

Pharmaceutical Preparation 2 (1) Compound of Example 4 50 mg (2) Lactose34 mg (3) Corn starch 10.6 mg (4) Corn starch (in paste form) 5 mg (5)Magnesium stearate 0.4 mg (6) Carboxymethyl cellulose calcium 20 mgTotal 120 mgIn accordance with conventional methods, the above (1) to (6) were mixedand tabletted by means of a tabletting machine to obtain a tablet.

Pharmaceutical Preparation 3 (1) Compound of Example 4  5.0 mg (2)Sodium chloride 20.0 mg (3) Distilled water To make the total amount 2ml

The compound of Example 4 (5.0 mg) and sodium chloride (20.0 mg) aredissolved in distilled water, and to the solution is added water to makethe total volume 2.0 ml. The solution is filtered, and filled into anampoule (content: 2 ml) under sterilized conditions. The ampoule issterilized, and sealed to obtain an injectable solution.

Pharmaceutical Preparation 4 (1) Compound of Example 11  5.0 mg (2)Sodium chloride 20.0 mg (3) Distilled water To make the total amount 2ml

The compound of Example 11 (5.0 mg) and sodium chloride (20.0 mg) aredissolved in distilled water, and to the solution is added water to makethe total volume 2 ml. The solution is filtered, and filled into anampoule (content: 2 ml) under sterilized conditions. The ampoule issterilized, and sealed to obtain an injectable solution.

Pharmaceutical Preparation 5 (1) Compound of Example 11 50 mg (2)Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste) 5 mg (5)Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total120 mgIn accordance with conventional methods, the above (1) to (6) were mixedand tabletted by means of a tabletting machine to obtain tablets.

Pharmaceutical Preparation 6 (1) Compound of Example 11  5.0 mg (2)Sodium chloride 20.0 mg (3) Distilled water To make the total amount 2ml

The compound of Example 11 (5.0 mg) and sodium chloride (20.0 mg) aredissolved in distilled water, and to the solution is added water to makethe total volume 2 ml. The solution is filtered, and filled into anampoule (content: 2 ml) under sterilized conditions. The ampoule issterilized, and sealed to obtain an injectable solution.

Pharmaceutical Preparation 7 (1) Compound of Example 12  5.0 mg (2)Sodium chloride 20.0 mg (3) Distilled water To make the total amount 2ml

The compound of Example 12 (5.0 mg) and sodium chloride (20.0 mg) aredissolved in distilled water, and to the solution is added water to makethe total volume 2 ml. The solution is filtered, and filled into anampoule (content: 2 ml) under sterilized conditions. The ampoule issterilized, and sealed to prepare an injectable solution.

Pharmaceutical Preparation 8 (1) Compound of Example 12 50 mg (2)Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste) 5 mg (5)Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total120 mgIn accordance with conventional methods, the above (1) to (6) are mixedand tabletted by means of a tabletting machine to obtain tablets.

Pharmaceutical Preparation 9 (1) Compound of Example 12  5.0 mg (2)Sodium chloride 20.0 mg (3) Distilled water To make the total amount 2ml

The compound of Example 12 (5.0 mg) and sodium chloride (20.0 mg) aredissolved in distilled water, and to the solution is added water to makethe total volume 2 ml. The solution is filtered, and filled into anampoule (content: 2 ml) under sterilized conditions. The ampoule issterilized, and sealed to prepare an injectable solution.

Test Example 1 AR-binding Inhibition Test (Wild type, LNCaP Type)

A solution of wild type or LNCaP type mutant androgen receptor, radiolabeled Mibolerone (final concentration 3 nM) and a compound (finalconcentration 0.001 to 10 μM) were mixed. The mixture was incubated at4° C. for 3 hours, and by the dextran/charcoal method, B (Bound) and F(Free) Mibolerone were separated. The radioactivity of B was measuredand IC₅₀ was calculated. The results are shown in Table 32. TABLE 32Compound wild type LNCaP type Compound of Example 1  190 nM  200 nMCompound of Example 4  7.8 nM  7.5 nM Compound of Example 80   40 nM  68 nM Bicalutamide   95 nM  305 nM

As is clear from Table 32, the compound of the present invention showeda strong affinity to both the wild type and LNCaP type mutant androgenreceptor.

Test Example 2 Inhibition Test of the Compound of the Present Inventionon Prostate-specific Antigen (PSA) Production in Various Prostate CancerCells Including Mutants

Human prostate cancer cells LNCaP-FGC were seeded in a 24-well plate ata concentration of 40,000 cells/ml/well or in a 96-well plate at aconcentration of 5000 cells/100 μl/well. On the following day,testosterone (final concentration 1 ng/ml) and a compound (finalconcentration 0.01 to 10 μM) were added. Three days after the addition,the concentration of PSA in the supernatant of the culture solution wasmeasured by ELISA, and IC₅₀ was calculated. The results are shown inTable 33. TABLE 33 Compound of Example 1 392 nM Compound of Example 4 87 nM Compound of Example 80  34 nM Bicalutamide 823 nM

As is clear from Table 33, the compounds of the present invention showeda strong PSA production suppressing activity.

Test Example 3 AR Transcription Inhibition Test

Cos-7 cells were inoculated in a flask at 5,000,000 cells, and incubatedin a culture solution (DMEM+10% Dextran Charcoal (DCC)-Fetal BovineSerum (FBS) +2 mM glutamine) for 24 hours. A vector DNA in which amutation type AR (W741C) gene was inserted and a vector DNA combinedwith luciferase gene downstream of the androgen responsive promoter werecotransfected by the liposome method. Two hours later, the culturemedium was replaced and incubation was further carried out for 3 hours.DHT (Dihydrotestosterone) at a final concentration 0.04 μM and a testcompound at a final concentration of 1 μM were added, and incubation wasfurther carried out for 24 hours. By measuring luciferase activity, ARtranscription inhibitory activity of the test compound was examined. Theresults are shown in Table 34 as inhibition rate (%) relative to thecontrol. TABLE 34 Inhibition rate (%) Compound of Example 1 64.3Compound of Example 4 20.1 Compound of Example 80 80.1 Bicalutamide 2.1

As is clear from Table 34, while bicalutamide showed almost notranscription inhibitory activity in mutant type AR (W741C), compoundsof the present invention showed a strong transcription inhibitoryactivity.

Industrial Applicability

The compound (I) or salt thereof of the present invention has a superiorantagonistic effect against normal androgen receptor and (or) a mutantandrogen receptor, and is useful as a prophylactic and therapeutic agentagainst hormone-sensitive cancers at androgen-dependent and (or)androgen-independent stages.

1. An androgen receptor antagonistic agent containing a compound of theformula:

wherein, R¹ is a hydrogen atom, a group binding through a carbon atom, agroup binding through a nitrogen atom, a group binding through an oxygenatom or a group binding through a sulfur atom, R² is a hydrogen atom, agroup binding through a carbon atom, a group binding through a nitrogenatom, a group binding through an oxygen atom or a group binding througha sulfur atom, R³ is a hydrogen atom, a hydrocarbon group which may havesubstituent(s), an acyl group or a heterocyclic group which may havesubstituent(s), R⁴ is a hydrogen atom, a group binding through a carbonatom, a group binding through a nitrogen atom, a group binding throughan oxygen atom or a group binding through a sulfur atom, R⁵ is a cyclicgroup which may have substituent(s), or a salt thereof, or its prodrug.2. An agent as claimed in claim 1, wherein R¹ is a hydrogen atom, acyano group, a hydrocarbon group which may have substituent(s), a grouprepresented by the formula: —COOR⁶¹ (wherein R⁶¹ is a hydrogen atom or ahydrocarbon group which may have substituent(s)), a group represented bythe formula: —CONR⁷¹R⁸¹ (wherein R⁷¹ and R⁸¹ are the same or different,each of them is a hydrogen atom or a hydrocarbon group which may havesubstituent(s), and R⁷¹ and R⁸¹ are combined with each other togetherwith the adjacent nitrogen atom to form a cyclic group which may havesubstituent(s)), a group represented by the formula: —COR⁹¹ (wherein R⁹¹is a hydrogen atom or a hydrocarbon group which may have substituent(s))or a group represented by the formula: —OR¹³¹ (wherein R¹³¹ is ahydrogen atom or a hydrocarbon group which may have substituent(s)). 3.An agent as claimed in claim 1, wherein R¹ is a cyano group or a grouprepresented by the formula: —COOR⁶¹ (wherein R⁶¹ is a hydrocarbon groupwhich may have substituent(s)).
 4. An agent as claimed in claim 1,wherein R² is a hydrogen atom, a cyano group, a hydrocarbon group whichmay have substituent(s), a group represented by the formula: —COOR⁶²:(wherein R⁶² is a hydrocarbon group which may have substituent(s)), agroup represented by the formula: —CONR⁷²R⁸² (wherein R⁷² and R⁸² arethe same or different, each of them is a hydrogen atom or a hydrocarbongroup which may have substituent(s), R⁷² and R⁸² are combined with eachother together with the adjacent nitrogen atom to form a cyclic groupwhich may have substituent(s)), a group represented by the formula:—COR⁹² (wherein R⁹² is a hydrogen atom or a hydrocarbon group which mayhave substituent(s)), or a group represented by the formula: —OR¹³²(wherein R¹³² is a hydrogen atom or a hydrocarbon group which may havesubstituent(s)).
 5. An agent as claimed in claim 1, wherein R² is a C₁₋₆alkyl group which may have substituent(s).
 6. An agent as claimed inclaim 1, wherein R³ is a C₁₋₆ alkyl group which may have substituent(s),a C₇₋₁₅ aralkyl group which may have substituent(s), a heterocyclicgroup-C₁₋₆ alkyl group which may have substituent(s), a C₁₋₆ alkylgroup-sulfonyl group which may have substituent(s), a C₆₋₁₄ arylgroup-sulfonyl group which may have substituent(s), a heterocyclicgroup-sulfonyl group which may have substituent(s), a C₁₋₆ alkylgroup-carbonyl group which may have substituent(s), a C₆₋₁₄ arylgroup-carbonyl group which may have substituent(s) or a heterocyclicgroup-carbonyl group which may have substituent(s).
 7. An agent asclaimed in claim 1, wherein R³ is a benzyl group which may havesubstituent(s) or a pyridylmethyl group which may have substituent(s).8. An agent as claimed in claim 1, wherein R³is a heterocyclicgroup-methyl group which may have substituent(s)).
 9. An agent asclaimed in claim 1, wherein R⁴ is a hydrogen atom, a cyano group, ahydrocarbon group which may have substituent(s), a group represented bythe formula: —COOR64 (wherein R⁶⁴ is a hydrogen atom or a hydrocarbongroup which may have substituent(s)), a group represented by theformula: —CONR⁷⁴R⁸⁴ (wherein R⁷⁴ and R⁸⁴ are the same or different, eachof them is a hydrogen atom or a hydrocarbon group which may havesubstituent(s), R⁷⁴ and R⁸⁴ are combined to each other together with theadjacent nitrogen atom to form a cyclic group which may havesubstituent(s)), a group represented by the formula: —COR⁹⁴ (wherein R⁹⁴is a hydrogen atom or a hydrocarbon group which may have substituent(s))or a group represented by the formula: —OR¹³⁴ (wherein R¹³⁴ is ahydrogen atom or a hydrocarbon group which may have substituent(s)). 10.An agent as claimed in claim 1, wherein R⁴ is a C₁₋₆ alkyl group whichmay have substituent(s).
 11. An agent as claimed in claim 1, wherein R⁵is a cyclic hydrocarbon group which may have substituent(s).
 12. Anagent as claimed in claim 1, wherein R⁵ is a C₆₋₁₄ aryl group which mayhave substituent(s) or a heterocyclic group which may havesubstituent(s).
 13. An agent as claimed in claim 1, wherein R⁵ is aC₆₋₁₄ aryl group which has at least one substituent selected from agroup consisting of a cyano group and a nitro group.
 14. An agent asclaimed in claim 1, wherein R¹ is a cyano group, a C₁₋₆ alkyl groupwhich may have hydroxy, a group represented by the formula: —COOR^(6′1)(wherein R^(6′1) is a C₁₋₆ alkyl group), a group represented by theformula: —CONR^(7′1)R^(8′1) (wherein R^(7′1) and R^(8′1) are the same ordifferent, each of them is a hydrogen atom, a C₁₋₆ alkyl group or aC₆₋₁₀ aryl group, R^(7′1) and R^(8′1) are taken together to form acyclic group which may have substituent(s)), a group represented by theformula: —COR^(9″1) (wherein R^(9″1) is a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group or a heterocyclic group which may have substituent(s)), R²and R⁴ are the same or different, and each of them is a hydrogen atom, acyano group or a C₁₋₆ alkyl group, R³ is a hydrogen atom or ahydrocarbon group which may have substituent(s) or a heterocyclic groupwhich may have substituent(s), R⁵ is an aryl group which may havesubstituent(s), a C₃₋₈ cyclo alkyl group which may have substituent(s)or a heterocyclic group which may have substituent(s).
 15. An agent asclaimed in claim 1, wherein R¹ is a cyano group or a group representedby the formula: —COOR^(6′1) (wherein R^(6′1) is a C₁₋₆ alkyl group), R²is a C₁₋₆ alkyl group which may have substituent(s), R³ is a C₁₋₆ alkylgroup which may have substituent(s), a C₇₋₁₅ is aralkyl group which mayhave substituent(s) a C₁₋₆ alkyl group-sulfonyl group which may havesubstituent(s) or a C₆₋₁₄ aryl group-carbonyl group which may havesubstituent(s), a R⁴ is a C₁₋₆ alkyl group which may havesubstituent(s), R⁵ is a C₆₋₁₄ aryl group which may have substituent(s).16. An agent as claimed in claim 1, wherein R¹ is a cyano group or agroup represented by the formula: —COOR^(6′1) (wherein R^(6′1) is a C₁₋₆alkyl group), R² is a C₁₋₆ alkyl group, R³ is a C₁₋₆ alkyl group whichmay have hydroxy, a C₇₋₁₅ aralkyl group, a C₁₋₆ alkyl group-sulfonylgroup or a C₆₋₁₄ aryl group-carbonyl group, R⁴ is a C₁₋₆ alkyl group,and R⁵ is a C₆₋₁₄ aryl group which may have a nitro group, a cyano groupor a C₁₋₃ acyl group.
 17. An agent as claimed in claim 1, wherein thecompound is a group represented by the formula:

wherein R^(1′) is a cyano group, a C₁₋₆ alkyl group, a group representedby the formula: —COOR^(6′1′) (wherein R^(6′1′) is a C₁₋₆ alkyl group), agroup represented by the formula: —CONR^(7′1′)R^(8′1′) (wherein R^(7′1′)and R^(8′1′) are the same or different, and each of them is a hydrogenatom, a C₁₋₆ alkyl group or a C₆₋₁₀ aryl group), a group represented bythe formula: —C(OH)R^(161′)R^(16′1′) (R^(161′) and R^(16′1′) are thesame or different, and each of them is a hydrogen atom or a C₁₋₆ alkyl)or a group represented by the formula: —COR^(9″1′) (wherein R^(9″1′) isa C₁₋₆ alkyl group, a C₃₋₈ cyclo alkyl group or a heterocyclic groupwhich may have substituent(s)), R¹⁷ is a C₆₋₁₄ aryl group which may havesubstituent(s) or a heterocyclic group which may have substituent(s),R¹⁸ is a nitro group, a C₁₋₆ alkyl group which may have substituent(s),a halogen atom, a C₁₋₆ alkoxy group, a cyano group, a carboxyl group, acarboxylic acid ester group, a hydroxy group or an amide group, X¹ is abivalent group in which number of straight-chained carbon atoms is 1 to5 which may have substituent(s); or a salt thereof, or its prodrug. 18.An agent as claimed in claim 1, wherein the compound is represented bythe formula:

wherein R^(1″) is a cyano group or a group represented by the formula:—COOR^(6″1″) (wherein R^(6″1″) is a methyl group or a ethyl group), R¹⁹is a C₆₋₁₄ aryl group which may have substituent(s) or a heterocyclicgroup which may have substituent(s), at least one of R²⁰ and R²¹ is anitro group or a cyano group, the ring A may further havesubstituent(s), and X² is a bivalent group in which the number ofstraight-chained carbon atom(s) is 1 to 5 which may have substituent(s);or a salt thereof, or its prodrug.
 19. An agent as claimed in claim 1,wherein the compound is one selected from the group consisting of (1)ethyl 1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylateor a salt thereof, (2) methyl1-benzyl-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate or asalt thereof, (3) methyl1-benzyl-4-(4-formylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate or asalt thereof, (4) methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole-3-carboxylateor a salt thereof, (5)4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole-3-carbonitrileor a salt thereof, (6)4-(4-cyanophenyl)-2,5-dimethyl-1-((6-methyl-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrileor a salt thereof and (7)4-(4-cyanophenyl)-2,5-dimethyl-1-((6-chloro-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrileor a salt thereof.
 20. An agent as claimed in claim 1, wherein theandrogen receptor is a normal androgen receptor and/or a mutant androgenreceptor.
 21. An agent as claimed in claim 1, which is a prophylactic ortherapeutic agent for hormone-sensitive cancer in androgen-dependentstage and/or androgen-independent stage.
 22. An agent as claimed inclaim 1, which is a prophylactic or therapeutic agent for prostatecancer.
 23. A compound represented by the formula:

wherein R^(1a) is a hydrogen atom, a group binding through a carbonatom, a group binding through a nitrogen atom, a group binding throughan oxygen atom or a group binding through a sulfur atom, R^(2a) is ahydrogen atom, a group binding through a carbon atom, a group bindingthrough a nitrogen atom, a group binding through an oxygen atom or agroup binding through a sulfur atom, R^(3a) is an aromatic ring groupwhich may have substituent(s), R^(4a) is a hydrogen atom, a groupbinding through a carbon atom, a group binding through a nitrogen atom,a group binding through an oxygen atom or a group binding through asulfur atom, at least one of R^(5a) and R^(5aa) is a nitro group, acyano group or a formyl group, the ring B may further havesubstituent(s), and X³ is a bivalent group in which the number ofstraight-chained carbon atom(s) is 1 to 5, which may havesubstituent(s); (provided that (1) ethyl4-(3-cyanophenyl)-1-(2-naphthylmethyl)-1H-pyrrole-3-carboxylate, (2)ethyl 4-(3-cyanophenyl)-1-(1-naphthylmethyl)-1H-pyrrole-3-carboxylate,(3) 1-benzyl-3-(3-nitrophenyl)-1H-pyrrole, (4)1-benzyl-3-methyl-4-(4-nitrophenyl)-1H-pyrrole,(5)tert-butyl4-ethyl-1-(4-nitrobenzyl)-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate,(6) tert-butyl4-ethyl-1-(4-methoxybenzyl)-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate,(7) tert-butyl1-benzyl-4-ethyl-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate, (8)tert-butyl 1-benzyl-4-methyl-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate,(9) methyl [4-(aminocarbonyl)-5-methyl-3-(4-nitrophenyl)-1-(2-pyridine-2-ylethyl)-1H-pyrrole-2-yl]acetate, (10)1-benzyl-N-{2′-[(tert-butylamino)sulfonyl]-1,1′-biphenyl-4-yl}-4-(3-cyanophenyl)-1H-pyrrole-3-carboxamide,(11) 3-{1-[(E)-1-cyano-2-(3,5-dichloro-1-methyl-1H-pyrazole-4-yl)-2-hydroxyethenyl]-1H-pyrrole-3-yl}benzonitrile, (12) methyl4-(4-amino-3-nitrophenyl)-1-benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylate,(13) methyl 1-benzoyl-4-(3-nitrophenyl)-1H-pyrrole-3-carboxylate, (14)4-[1-benzyl-2-(2-furanyl)-5-phenyl-1H-pyrrole-3-yl]-benzonitrile and(15) 4-[1-benzyl-2,5-diphenyl-1H-pyrrole-3-yl]-benzonitrile areexcluded) a salt thereof, or its prodrug.
 24. A compound as claimed inclaim 23, wherein X³ is a methylene group which may have substituent(s),R^(3a) is a C₆₋₁₄ aryl group which may have substituent(s), or a 5- to14-membered aromatic heterocyclic group which may have substituent(s) ora salt thereof, or its prodrug.
 25. A compound as claimed in claim 23,wherein X³ is a methylene group which may have substituent(s), andR^(3a) is a 5- to 14-membered aromatic heterocyclic group which may havesubstituent(s) or a salt thereof, or its prodrug.
 26. A compoundrepresented by the formula:

wherein R^(1b) is a cyano group or a group represented by the formula:—COOR^(6′1b) (wherein R^(6′1b) is a C₁₋₆ alkyl group), R^(2b) is ahydrogen atom or a C₁₋₆ alkyl group, R^(3b) is a C₁₋₆ alkyl group whichmay have substituent(s), a C₇₋₁₅ aralkyl group which may havesubstituent(s), a 5- to 14-membered aromatic heterocyclic group-C₁₋₆alkyl group, a group represented by the formula: —CO—R^(9′3b) (whereinR^(9′3b) is a C₁₋₆ alkyl group which may have substituent(s), a C₆₋₁₄aryl group which may have substituent(s) or a 5- to 14-membered aromaticheterocyclic group which may have substituent(s)) or a group representedby the formula: —SO₂—R^(12′3b) (wherein R^(12′3b) is a C₁₋₆ alkyl groupwhich may have substituent(s), a C₆₋₁₄ aryl group which may havesubstituent(s) or a 5- to 14-membered aromatic heterocyclic group whichmay have substituent(s)), R^(4b) is a hydrogen atom or a C₁₋₆ alkylgroup, at least one of R^(5b) and R^(5bb) is a nitro group, a cyanogroup or a formyl group; (provided (1) ethyl4-(3-cyanophenyl)-1-(2-naphthylmethyl)-1H-pyrrole-3-carboxylate, (2)ethyl 4-(3-cyanophenyl)-1-(1-naphthylmethyl)-1H-pyrrole-3-carboxylate,(3) methyl4-(4-amino-3-nitrophenyl)-1-benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylate,(4) methyl4-(4-amino-3-nitrophenyl)-1-butyl-2,5-dimethyl-1H-pyrrole-3-carboxylate,(5) methyl4-(4-amino-3-nitrophenyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate, (6)methyl 1-benzoyl-4-(3-nitrophenyl)-1H-pyrrole-3-carboxylate, (7)dimethyl 4-(3-nitrophenyl)-1H-pyrrole-1,3-dicarboxylate are excluded),its salt, or its prodrug.
 27. A compound as claimed in claim 26, whereinR^(1b) is a cyano group or a group represented by the formula:—COOR^(6′1b) (wherein R^(6′1b) is a C₁₋₆ alkyl group), R^(2b) is a C₁₋₆alkyl group, R^(3b) is a C₁₋₆ alkyl group which may have substituent(s),a C₇₋₁₅ aralkyl group which may have substituent(s), a 5- to 14-memberedaromatic heterocyclic group-C₁₋₆ alkyl group which may havesubstituent(s), a group represented by the formula: —CO—R^(9′3b)(wherein R^(9′3b) is a C₁₋₆ alkyl group which may have substituent(s), aC₆₋₁₄ aryl group which may have substituent(s) or a 5- to 14-memberedaromatic heterocyclic group which may have substituent(s)) or a grouprepresented by the formula: —SO₂—R^(12′3b) (wherein R^(12′3b) is a C₁₋₆alkyl group which may have substituent(s), a C₆₋₁₄ aryl group which mayhave substituent(s) or a 5- to 14-membered aromatic heterocyclic groupwhich may have substituent(s)), R^(4b) is a C₁₋₆ alkyl group, R^(5b) isa nitro group, a cyano group or a formyl group or a salt thereof, or itsprodrug.
 28. A compound as claimed in claim 26, wherein R^(3b) is aC₆₋₁₄ aryl-methyl group which may have substituent(s), or a 5- to14-membered aromatic heterocyclic group-methyl group which may havesubstituent(s) or a salt thereof, or its prodrug.
 29. A compound asclaimed in claim 26, wherein R^(3b) is a 5- to 14-membered aromaticheterocyclic group-methyl group which may have substituent(s) a saltthereof, or its prodrug.
 30. A compound as claimed in claim 26, whereinR^(1b) is a cyano group or a salt thereof, or its prodrug.
 31. Acompound as claimed in claim 26, wherein R^(3b) is a benzyl group whichmay have substituent(s) or a pyridylmethyl group which may havesubstituent(s) or a salt thereof, or its prodrug.
 32. A compoundselected from the group consisting of (1) ethyl1-benzyl-2,5-dimethyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate or itssalt, (2) methyl1-benzyl-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate or itssalt, (3) methyl1-benzyl-4-(4-formylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate or itssalt, (4) methyl4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole-3-carboxylate or its salt, (5)4-(4-cyanophenyl)-2,5-dimethyl-1-(3-pyridylmethyl)-1H-pyrrole-3-carbonitrileor its salt, (6)4-(4-cyanophenyl)-2,5-dimethyl-1-((6-methyl-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrileor its salt, and (7)4-(4-cyanophenyl)-2,5-dimethyl-1-((6-chloro-3-pyridyl)methyl)-1H-pyrrole-3-carbonitrileor its salt.
 33. A medicament containing a compound defined in claim 23or claim 26 or a salt thereof, or its prodrug.
 34. A medicament whichcomprises a compound represented by the formula:

wherein R¹ is a hydrogen atom, a group binding through a carbon atom, agroup binding through a nitrogen atom, a group binding through an oxygenatom or a group binding through a sulfur, atom, R² is a hydrogen atom, agroup binding through a carbon atom, a group binding through a nitrogenatom, a group binding through an oxygen atom or a group binding througha sulfur atom, R³ is a hydrogen atom, a hydrocarbon group which may havesubstituent(s), an acyl group or a heterocyclic group which may havesubstituent(s), R⁴ is a hydrogen atom, a group binding through a carbonatom, a group binding through a nitrogen atom, a group binding through aoxygen atom or a group binding through a sulfur atom, R⁵ is a cyclicgroup which may have substituent(s); or a salt thereof, or its prodrugand an anticancer drug in combination.
 35. A medicament as claimed inclaim 34, wherein the anticancer agent is an LH—RH derivative.
 36. Aprophylactic or therapeutic agent for a cancer sensitive to a hormone inandrogen-dependent stage and/or androgen-independent stage comprising amutant androgen receptor antagonistic drug.
 37. A prophylactic ortherapeutic agent for a cancer sensitive to a hormone inandrogen-dependent stage and/or androgen-independent stage whichcomprises mutant androgen receptor antagonistic drug and an anticanceragent.
 38. An agent as claimed in claim 37, wherein the anticancer agentis an LH—RH derivative.
 39. A prophylactic or therapeutic agent for acancer sensitive to a hormone in androgen-dependent stage and/orandrogen-independent stage containing a sensitivity-increased androgenreceptor antagonistic drug.
 40. A prophylactic or therapeutic agent fora cancer sensitive to a hormone in androgen-dependent stage and/orandrogen-independent stage which comprises a sensitivity-increasedandrogen receptor antagonistic drug and an anticancer agent.
 41. Aprophylactic or therapeutic agent as claimed in claim 40, wherein theanticancer agent is an LH—RH derivative.
 42. A method for antagonizingandrogen receptor, which comprises administering an effective amount ofa compound of the formula:

wherein R¹ is a hydrogen atom, a group binding through a carbon atom, agroup binding through a nitrogen atom, a group binding through an oxygenatom or a group binding through a sulfur atom, R² is a hydrogen atom, agroup binding through a carbon atom, a group binding through a nitrogenatom, a group binding through an oxygen atom or a group binding througha sulfur atom, R³ is a hydrogen atom, a hydrocarbon group which may havesubstituent(s), an acyl group or a heterocyclic group which may havesubstituent(s), R⁴ is a hydrogen atom, a group binding through a carbonatom, a group binding through a nitrogen atom, a group binding throughan oxygen atom or a group binding through a sulfur atom, R⁵ is a cyclicgroup which may have substituent(s); or a salt thereof, or its prodrug,to a mammal.
 43. A method for preventing or treating a cancer sensitiveto a hormone in androgen-dependent stage and/or androgen-independentstage, which comprises administering an effective amount of a compoundrepresented by the formula:

wherein R¹ is a hydrogen atom, a group binding through a carbon atom, agroup binding through a nitrogen atom, a group binding through an oxygenatom or a group binding through a sulfur atom, R² a hydrogen atom, agroup binding through a carbon atom, a group binding through a nitrogenatom, a group binding through an oxygen atom or a group binding througha sulfur atom, R³ is a hydrogen atom, a hydrocarbon group which may havesubstituent(s), an acyl group or a heterocyclic group which may havesubstituent(s), R⁴ is a hydrogen atom, a group binding through a carbonatom, a group binding through a nitrogen atom, a group binding throughan oxygen atom or a group binding through a sulfur atom, R⁵ is a cyclicgroup which may have substituent(s); or a salt thereof, or its prodrug,to a mammal.
 44. A method for preventing or treating prostate cancer,which comprises administering an effective amount of a compoundrepresented by the formula:

wherein R¹ is a hydrogen atom, a group binding through a carbon atom, agroup binding through a nitrogen atom, a group binding through an oxygenatom or a group binding through a sulfur atom, R² is a hydrogen atom, agroup binding through a carbon atom, a group binding through a nitrogenatom, a group binding through an oxygen atom or a group binding througha sulfur atom, R³ is a hydrogen atom, a hydrocarbon group which may havesubstituent(s), an acyl group or a heterocyclic group which may havesubstituent(s), R⁴ is a hydrogen atom, a group binding through a carbonatom, a group binding through a nitrogen atom, a group binding throughan oxygen atom or a group binding through a sulfur atom, R⁵ is a cyclicgroup which may have substituent(s); or a salt thereof, or its prodrug,to a mammal.
 45. A method as claimed in claim 43 and 44, in which aneffective amount of an anticancer agent is further administered.
 46. Amethod as claimed in claim 45, wherein the anticancer agent is an LH—RHderivative.
 47. A method for preventing or treating a cancer sensitiveto a hormone in androgen-dependent stage and/or androgen-independentstage, which comprise administering an effective amount of mutantandrogen receptor antagonistic drug to a mammal.
 48. A method as claimedin claim 47, in which an effective amount of an anticancer agent isfurther administered.
 49. A method as claimed in claim 48, wherein theanticancer agent is an LH—RH derivative.
 50. A method for preventing ortreating a cancer sensitive to a hormone in androgen-dependent stageand/or androgen-independent stage, which comprises administering aneffective amount of a sensitivity-increased androgen receptorantagonistic drug to a mammal.
 51. A method as claimed in claim 50, inwhich an effective amount of an anticancer agent is furtheradministered.
 52. A method as claimed in claim 51, wherein theanticancer agent is an LH—RH derivative.